Pyrimidine compounds as delta opioid receptor modulators

ABSTRACT

Disclosed are compounds, compositions and methods for treating various diseases, syndromes, conditions and disorders, including pain. Such compounds are represented by Formula I as follows: 
     
       
         
         
             
             
         
       
     
     wherein R 1 , R 2 , R 3 , and L, A, and R a  are defined herein.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application 61/256,405, filed on Oct. 30, 2009, which is incorporated by reference herein in its entirety.

FIELD OF THE INVENTION

The present invention is directed to novel opioid receptor modulators of Formula (I). The invention further relates to methods for preparing such compounds, pharmaceutical compositions containing them, and their use in the treatment of opioid modulated disorders.

BACKGROUND OF THE INVENTION

The term “opiate” has been used to designate pharmacologically active alkaloids derived from opium, e.g., morphine, codeine, and many semi-synthetic congeners of morphine. After the isolation of peptide compounds with morphine-like actions, the term opioid was introduced to refer generically to all drugs with morphine-like actions. Included among opioids are various peptides that exhibit morphine-like activity, such as endorphins, enkephalins and dynorphins. However, some sources use the term “opiate” in a generic sense, and in such contexts, opiate and opioid are interchangeable. Additionally, the term opioid has been used to refer to antagonists of morphine-like drugs as well as to characterize receptors or binding sites that combine with such agents.

Opioids are generally employed as analgesics, but they may have many other pharmacological effects as well. Morphine and related opioids produce certain of their major effects on the central nervous and digestive systems. The effects are diverse, including analgesia, drowsiness, mood changes, respiratory depression, dizziness, mental clouding, dysphoria, pruritus, increased pressure in the biliary tract, decreased gastrointestinal motility, nausea, vomiting, and alterations of the endocrine and autonomic nervous systems.

When therapeutic doses of morphine are given to patients with pain, they report that the pain is less intense, less discomforting, or entirely gone. In addition to experiencing relief of distress, some patients experience euphoria. However, when morphine in a selected pain-relieving dose is given to a pain-free individual, the experience is not always pleasant; nausea is common, and vomiting may also occur. Drowsiness, inability to concentrate, difficulty in mentation, apathy, lessened physical activity, reduced visual acuity, and lethargy may ensue.

Two distinct classes of opioid molecules can bind opioid receptors: the opioid peptides (e.g., the enkephalins, dynorphins, and endorphins) and the alkaloid opiates (e.g., morphine, etorphine, diprenorphine and naloxone). Subsequent to the initial demonstration of opiate binding sites (Pert, C. B. and Snyder, S. H., Science (1973) 179:1011-1014), the differential pharmacological and physiological effects of both opioid peptide analogues and alkaloid opiates served to delineate multiple opioid receptors. Accordingly, three molecularly and pharmacologically distinct opioid receptor types have been described: delta, kappa and mu. Furthermore, each type is believed to have sub-types (Wollemann, M., J Neurochem (1990) 54:1095-1101; Lord, J. A., et al., Nature (1977) 267:495-499).

All three of these opioid receptor types appear to share the same functional mechanisms at a cellular level. For example, the opioid receptors cause inhibition of adenylate cyclase, and inhibition of neurotransmitter release via both potassium channel activation and inhibition of Ca²⁺ channels (Evans, C. J., In: Biological Basis of Substance Abuse, S. G. Korenman & J. D. Barchas, eds., Oxford University Press (in press); North, A. R., et al., Proc Natl Acad Sci USA (1990) 87:7025-29; Gross, R. A., et al., Proc Natl Acad Sci USA (1990) 87:7025-29; Sharma, S. K., et al., Proc Natl Acad Sci USA (1975) 72:3092-96). Although the functional mechanisms are the same, the behavioral manifestations of receptor-selective drugs differ greatly (Gilbert, P. E. & Martin, W. R., J Pharmacol Exp Ther (1976) 198:66-82). Such differences may be attributable in part to the anatomical location of the different receptors.

Delta receptors have a more discrete distribution within the mammalian CNS than either mu or kappa receptors, with high concentrations in the amygdaloid complex, striatum, substantia nigra, olfactory bulb, olfactory tubercles, hippocampal formation, and the cerebral cortex (Mansour, A., et al., Trends in Neurosci (1988) 11:308-14). The rat cerebellum is remarkably devoid of opioid receptors including delta opioid receptors.

There is a continuing need for new delta opioid receptor modulators as analgesics. There is a further need for delta opioid receptor selective agonists as analgesics having reduced side effects. There is also a need for delta opioid receptor antagonists as immunosuppressants, antiinflammatory agents, agents for the treatment of neurological and psychiatric conditions, agents for the treatment of urological and reproductive conditions, medicaments for drug and alcohol abuse, agents for treating gastritis and diarrhea, cardiovascular agents and agents for the treatment of respiratory diseases, having reduced side effects.

There is a continuing need for new opioid receptor modulators as analgesics. There is a further need for delta and mu opioid receptor agonists as analgesics having reduced side effects. There is a further need for mu opioid receptor agonists as analgesics having reduced side effects for the treatment of pain, immune function, esophageal reflux, and cough. There is also a need for delta opioid receptor agonists as analgesic agents, agents for the treatment of respiratory diseases, cardiovascular agents, agents for treating urological dysfunction, and agents for the treatment of neurological and psychiatric conditions. There is further need for dual delta opioid receptor/mu opioid receptor agonists.

SUMMARY OF THE INVENTION

The present invention is directed to a compound of Formula I

-   wherein -   R₁ is selected from the group consisting of -   i) phenyl optionally substituted with one to two substituents     independently selected from the group consisting of C₁₋₄alkyl,     C₂₋₄alkenyl, C₂₋₄alkynyl, C₁₋₄alkoxy, C₁₋₄alkylthio, hydroxy,     chloro, and fluoro; in addition, phenyl is optionally substituted     with a single amino, C₁₋₄alkylamino, di(C₁₋₄alkyl)amino,     di(C₁₋₄alkyl)aminocarbonyl, C₁₋₄alkylaminocarbonyl,     hydroxy(C₁₋₄)alkyl, aminocarbonyl, C₁₋₄alkylcarbonylamino,     C₁₋₄alkoxycarbonylamino, ureido, C₁₋₄alkylureido,     di(C₁₋₄alkyl)ureido, cyano, trifluoromethoxy, C₁₋₄alkylsulfonyl,     nitro, trifluoromethyl, bromo, piperazin-1-yl optionally substituted     with 4-C₁₋₄alkyl, morpholin-4-yl, phenyl, formamido, or pyridinyl     substituent;     -   and wherein the phenyl and pyridinyl substituents of the         R₁-phenyl are each optionally substituted with one substituent         selected from the group consisting of C₁₋₄alkyl, C₁₋₄alkoxy,         C₁₋₄alkylthio, fluoro, chloro, cyano, amino, and hydroxy; -   ii) pyrimidinyl optionally substituted with one to two substituents     independently selected from the group consisting of C₁₋₄alkyl,     C₁₋₄alkoxy, C₁₋₄alkylthio, and hydroxy; in addition, pyrimidinyl is     optionally substituted with a single amino, C₁₋₄alkylamino,     di(C₁₋₄alkyl)amino, di(C₁₋₄alkyl)aminocarbonyl,     C₁₋₄alkylaminocarbonyl, hydroxy(C₁₋₄)alkyl, aminocarbonyl,     C₁₋₄alkylcarbonylamino, C₁₋₄alkoxycarbonylamino, ureido,     C₁₋₄alkylureido, di(C₁₋₄alkyl)ureido, cyano, trifluoromethoxy,     C₁₋₄alkylsulfonyl, nitro, trifluoromethyl, bromo, piperazin-1-yl     optionally substituted with 4-C₁₋₄alkyl, morpholin-4-yl, formamido,     pyrrol-1-yl, phenyl, pyridinyl, or piperidin-1-yl substituent;     -   and, wherein the phenyl and pyridinyl substituents of the         R₁-pyrimidinyl are optionally independently substituted with one         to two substituents selected from the group consisting of         C₁₋₄alkyl, C₁₋₄alkoxy, C₁₋₄alkylthio, fluoro, chloro, cyano,         amino, and hydroxy; -   iii) pyridinyl optionally substituted with one to two substituents     independently selected form the group consisting of C₁₋₄alkyl,     C₁₋₄alkoxy, C₁₋₄alkylthio, hydroxy, fluoro, chloro, and cyano; in     addition, pyridinyl is optionally substituted with a single     hydroxymethyl, amino, C₁₋₄alkylamino, di(C₁₋₄alkyl)amino,     C₁₋₄alkylsulfonyl, aminocarbonyl, C₁₋₄alkylaminocarbonyl,     di(C₁₋₄alkyl)aminocarbonyl, C₁₋₄alkylcarbonylamino,     C₁₋₄alkoxyaminocarbonyl, ureido, C₁₋₄alkylureido,     di(C₁₋₄alkyl)ureido, piperazin-1-yl, morpholin-4-yl, phenyl, or     pyridinyl substituent;     -   and, wherein the phenyl and pyridinyl substituents of the         R₁-pyridinyl are optionally independently substituted with one         to two substituents selected from the group consisting of         C₁₋₄alkyl, C₁₋₄alkoxy, C₁₋₄alkylthio, fluoro, chloro, cyano,         amino, and hydroxy; and -   iv) a G-substituent selected from the group consisting of naphthyl,     pyrazolyl, thienyl, benzothiazolyl, benzimidazolyl, quinolinyl,     indolyl, thiazolyl, furanyl, dihydrobenzofuranyl, pyrazinyl,     isoquinolinyl, quinoxalinyl, quinazolinyl, isoxazolyl, oxazolyl,     pyrrolopyridinyl, benzo[1,3]dioxol-5-yl, benzo[1,2,5]oxadiazolyl,     dibenzothiophenyl, 4H-[1,2,4]oxadiazol-5-on-yl, benzothiophenyl,     indazolyl, and 2,3-dihydrobenzo[1,4]dioxinyl;     -   wherein G is optionally independently substituted with one to         two substituents selected from the group consisting of         C₁₋₄alkyl, C₁₋₄alkoxy, fluoro, chloro, bromo, cyano,         C₁₋₄alkylcarbonyl, amino, C₁₋₄alkylamino, and         di(C₁₋₄alkyl)amino; -   R₂ is -   (i) phenyl optionally substituted with one to three substituents     independently selected from the group consisting of C₁₋₄alkyl,     C₁₋₄alkoxy, C₁₋₄alkylthio, fluoro, chloro, and hydroxy; in addition,     phenyl of R₂ is optionally substituted with a single amino,     C₁₋₄alkylamino, di(C₁₋₄alkyl)amino, fluoromethyl, difluoromethyl,     trifluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy,     formamidino, aminocarbonyl, C₁₋₄alkylaminocarbonyl,     di(C₁₋₄)alkylaminocarbonyl, C₁₋₄alkylcarbonylamino,     2,2,2-trifluoroethoxy, cyano, C₃₋₇cycloalkylcarbonylamino,     hydroxy(C₁₋₄)alkyl, C₁₋₄alkoxy(C₁₋₄)alkyl, C₁₋₄alkoxy-(C₁₋₄)alkoxy,     C₁₋₄alkylcarbonyloxy, C₁₋₄alkylsulfonylamino, C₁₋₄alkylsulfonyl,     pyridinyl(C₁₋₄)alkyl, benzyloxycarbonylamino,     4-methyl-piperazin-1-ylcarbonyl, pyrrolidin-1-ylcarbonyl, carboxy,     piperidin-1-ylcarbonyl, morpholin-4-ylcarbonyl, C₃₋₇cycloalkyl,     C₃₋₇cycloalkyl-(C₁₋₃)alkyl, or C₃₋₇cycloalkyl-(C₁₋₃)alkoxy     substituent; -   (ii) 1,2-dihydrobenzofuranyl, bound to O of Formula (I) at the benzo     portion of the ring; and wherein the benzo portion of     1,2-dihydrobenzofuranyl is optionally independently substituted with     one to two substituents selected from the group consisting of     C₁₋₄alkyl, fluoro, chloro, bromo, cyano, C₁₋₄alkylcarbonyl, amino,     C₁₋₄alkylamino, and di(C₁₋₄alkylamino; -   or -   (iii) heteroaryl selected from the group consisting of     benzothiazolyl, benzooxazolyl, pyridinyl, pyrimidinyl, indazolyl,     quinolinyl, quinazolinyl, benzimidazolyl, pyrazinyl, triazinyl,     benzothiophenyl, benzofuranyl, and isoquinolinyl;     -   wherein heteroaryl of R₂ is optionally independently substituted         with one to two substituents selected from the group consisting         of C₁₋₄alkyl, fluoro, chloro, bromo, cyano, C₁₋₄alkylcarbonyl,         amino, C₁₋₄alkylamino, and di(C₁₋₄alkylamino; -   A-L- is selected from the group consisting of a₁-L₁-; a₂-L₂-;     a₃-L₃-; a₄-L₄-; and a₅-L₅-; wherein L₁ is absent or C₁₋₄alkyl; -   a₁ is bound through a carbon atom to L₁ and is selected from the     group consisting of -   i) pyrrolidinyl optionally substituted at carbon with C₁₋₄alkyl,     amino, C₁₋₄alkylamino, di(C₁₋₄alkyl)amino, aminomethyl, hydroxy,     cyano, C₁₋₄alkoxy, C₁₋₄alkoxycarbonyl, or one to two fluoro     substituents; and wherein pyrrolidinyl is optionally substituted at     nitrogen with C₁₋₄alkyl, phenyl(C₁₋₄)alkyl, C₁₋₄alkylcarbonyl,     C₁₋₄alkoxycarbonyl, or phenyl(C₁₋₄alkoxycarbonyl; -   ii) piperidinyl optionally substituted with C₁₋₄alkyl, phenyl,     amino, C₁₋₄alkylamino, di(C₁₋₄alkyl)amino, aminomethyl, hydroxy,     cyano, C₁₋₄alkoxy, C₁₋₄alkoxycarbonyl, phenyl(C₁₋₄)alkyl,     C₁₋₄alkylcarbonyl, or phenyl(C₁₋₄)alkoxycarbonyl; -   and -   iii) azetidinyl optionally substituted with 3-amino, 3-hydroxy,     3-C₁₋₄alkoxy, C₁₋₄alkyl, or aminomethyl;     -   provided that when L₁ is absent, a₁ is attached to N(R_(a)) via         a carbon atom other than that which is alpha to a nitrogen atom         of a₁;     -   and provided that when a₁ is substituted with a substituent         containing an oxygen or nitrogen radical as a point of         attachment to a₁, the substitution is at a carbon atom other         than that alpha to a nitrogen atom of a₁; -   L₂ is C₁₋₄alkyl; -   a₂ is bound through a carbon atom to L₂ and is selected from the     group consisting of -   i) piperazinyl optionally substituted at carbon with C₁₋₄alkyl,     aminomethyl, cyano, or C₁₋₄alkoxycarbonyl; and wherein piperazinyl     is optionally substituted at nitrogen with C₁₋₄alkyl,     phenyl(C₁₋₄)alkyl, C₁₋₄alkylcarbonyl, C₁₋₄alkoxycarbonyl, or     phenyl(C₁₋₄)alkoxycarbonyl; -   and -   ii) morpholinyl optionally independently substituted with     phenyl(C₁₋₄)alkyl or one to two C₁₋₄alkyl substituents; -   L₃ is methylene; -   a₃ is imidazolyl optionally independently substituted with one to     two C₁₋₄alkyl substituents; -   L₄ is (C₂₋₆)alkyl; and when L₄ is C₃₋₆alkyl, L₄ is optionally     substituted with chloro, hydroxy or C₁₋₄alkoxy; provided that the     chloro, hydroxy, and C₁₋₄alkoxy substituents are not alpha to a     nitrogen-bearing carbon atom; -   a₄ is selected from the group consisting of amino and     C₁₋₄alkylamino; -   provided that a₄ is attached at a carbon atom other than that alpha     to N(R_(a)); -   L₅ is absent or C₁₋₄alkyl; -   a₅ is C₃₋₇cycloalkyl substituted with R_(B); wherein R_(B) is     selected from the group consisting of amino, C₁₋₄alkylamino,     di(C₁₋₄alkyl)amino, aminomethyl, C₁₋₄alkylamino-methyl, and     di(C₁₋₄alkyl)amino-methyl; -   provided that when R_(B) contains a nitrogen radical as the point of     attachment to C₃₋₇cycloalkyl, the attachment is at a carbon atom     other than that alpha to N(R_(a)); -   or, -   A-L- is taken with R_(a) and the nitrogen atom to which they are     both attached to form a nitrogen-bound heterocyclyl selected from     the group consisting of -   i) pyrrolidinyl wherein pyrrolidinyl is optionally substituted with     C₁₋₄alkyl, amino, C₁₋₄alkylamino, di(C₁₋₄alkyl)amino, aminomethyl,     cyano, C₁₋₄alkoxy, C₁₋₄alkoxycarbonyl, or phenyl; -   ii) piperazinyl optionally substituted with 4-C₁₋₄alkyl; and wherein     piperazinyl is optionally independently substituted at carbon with     one to two C₁₋₄alkyl substituents, 2-oxo, 3-oxo, trifluoromethyl,     aminomethyl, or hydroxymethyl; -   iii) piperidinyl optionally substituted with one to two C₁₋₄alkyl     substituents, amino, C₁₋₄alkylamino, di(C₁₋₄alkyl)amino,     aminomethyl, hydroxy, cyano, C₁₋₄alkoxy, C₁₋₄alkoxycarbonyl, phenyl,     phenyl(C₁₋₄)alkyl, or one to two fluoro substituents; and, wherein     the phenyl and the phenyl portion of phenyl(C₁₋₄)alkyl are     optionally substituted with C₁₋₄alkyl, C₁₋₄alkoxy, C₁₋₄alkylthio,     fluoro, chloro, cyano, amino, or hydroxy; -   iv) azetidinyl optionally substituted with 3-amino or 3-aminomethyl; -   v) [1,4]diazepan-1-yl optionally substituted with one to two     C₁₋₄alkyl substituents; -   and -   vi) 3,6-diazoabicyclo[3.1.1]hept-3-yl optionally independently     substituted with one to two C₁₋₄alkyl substituents; -   R_(a) is hydrogen or C₁₋₄alkylcarbonyl; -   provided that a compound of Formula (I) is other than a compound     selected from the group consisting of -   a compound wherein R₁ is 4-fluoro-phenyl, R₂ is 4-methoxy-phenyl,     A-L- is a₁-L₁, a₁ is (S)-pyrrolidin-2-yl, L₁ is methyl, R_(a) is H,     and X is O; -   a compound wherein R₁ is pyrimidin-5-yl, R₂ is 4-methoxy-phenyl,     A-L- is a₂-L₂, a₂ is (S)-morpholin-3-yl, L₂ is methyl, R_(a) is H,     and X is O; a compound wherein R₁ is 5-fluoro-pyridin-3-yl, R₂ is     4-(piperidin-1-ylcarbonyl)-phenyl, A-L- is a₁-L₁, a₁ is     (S)-pyrrolidin-2-yl, L₁ is methyl, R_(a) is H, and X is O; -   a compound wherein R₁ is 5-fluoro-pyridin-3-yl, R₂ is     4-(4-methyl-piperazin-1-ylcarbonyl)-phenyl, A-L- is a₁-L₁, a₁ is     (S)-pyrrolidin-2-yl, L₁ is methyl, R_(a) is H, and X is O; -   a compound wherein R₁ is 5-cyano-pyridin-3-yl, R₂ is     2-methyl-phenyl, A-L- is a₁-L₁, a₁ is (S)-pyrrolidin-2-yl, L₁ is     methyl, R_(a) is H, and X is O; -   a compound wherein R₁ is pyridin-3-yl, R₂ is 4-methoxy-phenyl, A-L-     is a₅-L₅, a₅ is cyclohexyl, L₅ is absent, R_(B) is 2-amino, R_(a) is     H, and X is O; -   and -   a compound wherein R₁ is 5-fluoro-pyridin-3-yl, R₂ is     4-diethylaminocarbonyl-phenyl, A-L- is a₁-L₁, a₁ is     (S)-pyrrolidin-2-yl, L₁ is methyl, R_(a) is H, and X is O; -   and enantiomers, diastereomers, solvates, and pharmaceutically     acceptable salts thereof.

The present invention is also directed to a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of Formula (I) or a pharmaceutically acceptable salt form thereof.

Also provided are processes for making a pharmaceutical composition comprising mixing a compound of Formula (I) and a pharmaceutically acceptable carrier.

The present invention is further directed to methods for treating or ameliorating an opioid receptor-modulated disorder. In particular, the methods of the present invention are directed to treating or ameliorating a opioid receptor-modulated disorder including, but not limited to, inflammatory pain, centrally mediated pain, peripherally mediated pain, visceral pain, structural related pain, cancer/pain, soft tissue injury related pain, progressive disease related pain, neuropathic pain and acute pain from acute injury, acute pain from trauma, acute pain from surgery, chronic pain from headache, chronic pain from neuropathic conditions, chronic pain from post-stroke conditions and chronic pain from migraine.

The present invention also provides methods for producing the instant compounds and pharmaceutical compositions and medicaments thereof.

DETAILED DESCRIPTION OF THE INVENTION

As used herein, the following terms are intended to have the following meanings:

“C_(a-b)” (where a and b are integers) refers to a radical containing from a to b carbon atoms inclusive. For example, C₁₋₃ denotes a radical containing 1, 2 or 3 carbon atoms.

With reference to substituents, the term “independently” means that when more than one of such substituent is possible, such substituents may be the same or different from each other. Therefore, designated numbers of carbon atoms (e.g. C₁₋₈) shall refer independently to the number of carbon atoms in an alkyl or cycloalkyl moiety or to the alkyl portion of a larger substituent in which alkyl appears as its prefix root.

As used herein, unless otherwise noted, “alkyl” whether used alone or as part of a substituent group refers to straight and branched carbon chains having 1 to 8 carbon atoms or any number within this range. The term “alkoxy” refers to an -Oalkyl substituent group, wherein alkyl is as defined supra. Similarly, the terms “alkenyl” and “alkynyl” refer to straight and branched carbon chains having 2 to 8 carbon atoms or any number within this range, wherein an alkenyl chain has at least one double bond in the chain and an alkynyl chain has at least one triple bond in the chain. An alkyl and alkoxy chain may be substituted on a carbon atom. In substituent groups with multiple alkyl groups such as (C₁₋₆alkyl)₂amino- the C₁₋₆alkyl groups of the dialkylamino may be the same or different.

“Halogenated alkyl” refers to a saturated branched or straight chain alkyl radical derived by removal of 1 hydrogen atom from the parent alkane; the parent alkyl chain contains from 1 to 8 carbon atoms with 1 or more hydrogen atoms replaced with halogen atoms up to and including replacement of all hydrogen atoms with halogen. Preferred halogenated alkyl groups include trifluoromethyl substituted alkyls, difluoromethyl substituted alkyls, and perfluorinated alkyls; more preferred fluorinated alkyls include trifluoromethyl and difluoromethyl.

“Halogenated alkoxy” refers to a radical derived from a halogenated alkyl, radical attached to an oxygen atom with the oxygen atom having one open valence for attachment to a parent structure.

The term “cycloalkyl” refers to saturated or partially unsaturated, moncyclic or polycyclic hydrocarbon of from 3 to 20 carbon atom members (preferably from 3 to 14 carbon atom members). Examples of such groups include, and are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or adamantyl. The term cycloalkyl includes a cycloalkyl ring fused to a benzene ring (benzo fused cycloalkyl), or a 5 or 6 membered heteroaryl ring (containing one of O, S or N and, optionally, one additional nitrogen) to form a heteroaryl fused cycloalkyl.

The term “heterocyclyl” refers to a nonaromatic monocyclic ring of 5 to 10 members in which 1 to 4 members are nitrogen or a nonaromatic monocyclic ring of 5 to 10 members in which zero, one or two members are nitrogen and up to two members are oxygen or sulfur; wherein, optionally, the ring contains zero, one or two unsaturated bonds. The term heterocyclyl includes a heterocyclyl ring fused to a benzene ring (benzo fused heterocyclyl), a 5 or 6 membered heteroaryl ring (containing one of O, S or N and, optionally, one additional nitrogen), a 5 to 7 membered cycloalkyl or cycloalkenyl ring, a 5 to 7 membered heterocyclyl ring (of the same definition as above but absent the option of a further fused ring) or fused with the carbon of attachment of a cycloalkyl, cycloalkenyl or heterocyclyl ring to form a spiro moiety. For instant compounds of the invention, the carbon atom ring members that form the heterocyclyl ring are fully saturated. Other compounds of the invention may have a partially saturated heterocyclyl ring. Additionally, heterocyclyl includes a heterocyclic ring bridged to form bicyclic rings. Preferred partially saturated heterocyclyl rings may have from one to two double bonds. Such compounds are not considered to be fully aromatic and are not referred to as heteroaryl compounds. Examples of heterocyclyl groups include, and are not limited to, pyrrolinyl (including 2H-pyrrole, 2-pyrrolinyl or 3-pyrrolinyl), pyrrolidinyl, 2-imidazolinyl, imidazolidinyl, 2-pyrazolinyl, pyrazolidinyl, piperidinyl, morpholinyl, thiomorpholinyl and piperazinyl.

The term “aryl” refers to an unsaturated, aromatic monocyclic ring of 6 carbon members or to an unsaturated, aromatic polycyclic ring of from 10 to 14 carbon members. Examples of such aryl rings include, and are not limited to, phenyl, naphthalenyl or anthracenyl. Preferred aryl groups for the practice of this invention are phenyl and naphthalenyl.

The term “heteroaryl” refers to an aromatic ring of 5 or 6 members wherein the ring consists of carbon atoms and has at least one heteroatom member. Suitable heteroatoms include nitrogen, oxygen or sulfur. In the case of 5 membered rings, the heteroaryl ring contains one member of nitrogen, oxygen or sulfur and, in addition, may contain up to three additional nitrogens. In the case of 6 membered rings, the heteroaryl ring may contain from one to three nitrogen atoms. For the case wherein the 6 membered ring has three nitrogens, at most two nitrogen atoms are adjacent. The term heteroaryl includes a heteroaryl ring fused to a benzene ring (benzofused heteroaryl), a 5 or 6 membered heteroaryl ring (containing one of O, S or N and, optionally, one additional nitrogen), a 5 to 7 membered cycloalkyl ring or a 5 to 7 membered heterocyclic ring (as defined supra but absent the option of a further fused ring). Examples of heteroaryl groups include, and are not limited to, furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl or pyrazinyl; fused heteroaryl groups include indolyl, isoindolyl, benzofuryl, benzothienyl, indazolyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, benzisoxazolyl, benzothiadiazolyl, benzotriazolyl, quinoxalinyl, quinolinyl, isoquinolinyl or quinazolinyl.

The term “arylalkyl” means an alkyl group substituted with an aryl group (e.g., benzyl, phenethyl). Similarly, the term “arylalkoxy” indicates an alkoxy group substituted with an aryl group (e.g., benzyloxy).

The term “halogen” refers to fluorine, chlorine, bromine and iodine. Substituents that are substituted with multiple halogens are substituted in a manner that provides compounds, which are stable.

The term “oxo” whether used alone or as part of a substituent group refers to an O═ to either a carbon or a sulfur atom. For example, phthalimide and saccharin are examples of compounds with oxo substituents.

Whenever the term “alkyl” or “aryl” or either of their prefix roots appear in a name of a substituent (e.g., arylalkyl, alkylamino) it shall be interpreted as including those limitations given above for “alkyl” and “aryl.” Designated numbers of carbon atoms (e.g., C₁-C₆) shall refer independently to the number of carbon atoms in an alkyl moiety or to the alkyl portion of a larger substituent in which alkyl appears as its prefix root. For alkyl, and alkoxy substituents the designated number of carbon atoms includes all of the independent member included in the range specified individually and all the combination of ranges within in the range specified. For example C₁₋₆ alkyl would include methyl, ethyl, propyl, butyl, pentyl and hexyl individually as well as sub-combinations thereof (e.g. C₁₋₂, C₁₋₃, C₁₋₄, C₁₋₅, C₂₋₆, C₃₋₆, C₄₋₆, C₅₋₆, C₂₋₅, etc.).

The term “subject” as used herein, refers to an animal, preferably a mammal, most preferably a human, who has been the object of treatment, observation or experiment.

The term “therapeutically effective amount” as used herein, means that amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician, which includes alleviation of the symptoms of the disease or disorder being treated.

As used herein, the term “composition” is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combinations of the specified ingredients in the specified amounts.

As used herein, the term “acyl” refers to alkylcarbonyl substituents.

As used herein, the term “a carbon atom which is alpha (α) to a nitrogen atom” is defined as a carbon atom that is adjacent to, and covalently bound to, a nitrogen atom, as illustrated hereinbelow.

Throughout this disclosure, the terminal portion of the designated side chain is described first, followed by the adjacent functionality toward the point of attachment. Thus, for example, a “phenyl(C₁₋₆)alkylaminocarbonyl(C₁₋₆)alkyl” substituent refers to a group of the formula

Unless otherwise noted, it is intended that the definition of any substituent or variable at a particular location in a molecule be independent of its definitions elsewhere in that molecule. It is understood that substituents and substitution patterns on the compounds of formula (I) can be selected by one of ordinary skill in the art to provide compounds that are chemically stable and that can be readily synthesized by techniques known in the art as well as those methods set forth herein.

For purposes of the present invention, the term “opioid receptor-modulated” is used to refer to the condition of being affected by the modulation of an opioid receptor, including but not limited to, the state of being mediated by the opioid receptor.

DETAILED DESCRIPTION OF THE INVENTION

Embodiments of the present invention include those compounds of Formula (I) wherein

-   a) R₁ is selected from the group consisting of -   i) phenyl optionally substituted with one to two substituents     independently selected from the group consisting of C₁₋₄alkyl,     C₁₋₄alkoxy, hydroxy, chloro, and fluoro; in addition, phenyl is     optionally substituted with a single amino, di(C₁₋₄alkyl)amino,     di(C₁₋₄alkyl)aminocarbonyl, hydroxy(C₁₋₄)alkyl, aminocarbonyl,     C₁₋₄alkylcarbonylamino, cyano, trifluoromethoxy, C₁₋₄alkylsulfonyl,     nitro, trifluoromethyl, or phenyl substituent;     -   ii) pyrimidinyl optionally substituted with one to two         substituents independently selected from the group consisting of         C₁₋₄alkoxy, C₁₋₄alkylthio, and hydroxy; in addition, pyrimidinyl         is optionally substituted with a single cyano, morpholin-4-yl,         amino, di(C₁₋₄alkyl)amino, or piperazin-1-yl optionally         substituted with 4-C₁₋₄alkyl substituent;     -   iii) pyridinyl optionally substituted with one to two         substituents independently selected from the group consisting of         C₁₋₄alkyl, C₁₋₄alkoxy, C₁₋₄alkylthio, hydroxy, fluoro, chloro,         and cyano; in addition, pyridinyl is optionally substituted with         a single hydroxymethyl, amino, aminocarbonyl, C₁₋₄alkylsulfonyl,         or pyridinyl substituent;         -   wherein the pyridinyl substituent of the R₁-pyridinyl is             optionally independently substituted with one to two             substituents selected from the group consisting of chloro             and methyl;     -   and     -   iv) a G-substituent selected from the group consisting of         naphthyl, pyrazolyl, thienyl, benzothiazolyl, quinolinyl,         indolyl, thiazolyl, furanyl, dihydrobenzofuranyl, pyrazinyl,         quinoxalinyl, oxazolyl, pyrrolopyridinyl, benzo[1,3]dioxol-5-yl,         benzo[1,2,5]oxadiazolyl, dibenzothiophenyl,         4H-[1,2,4]oxadiazol-5-on-yl, and benzothiophenyl;     -   wherein G is optionally independently substituted with one to         two substituents selected from the group consisting of         C₁₋₄alkyl, fluoro, and chloro; -   b) R₁ is selected from the group consisting of     -   i) phenyl optionally substituted with one to two substituents         independently selected from the group consisting of C₁₋₄alkyl,         C₁₋₄alkoxy, hydroxy, chloro, and fluoro; in addition, phenyl is         optionally substituted with a single amino, di(C₁₋₄alkyl)amino,         di(C₁₋₄alkyl)aminocarbonyl, hydroxy(C₁₋₄)alkyl, aminocarbonyl,         C₁₋₄alkylcarbonylamino, cyano, trifluoromethoxy,         C₁₋₄alkylsulfonyl, nitro, trifluoromethyl, or phenyl         substituent;     -   ii) pyrimidinyl optionally substituted with one to two         substituents independently selected from the group consisting of         C₁₋₄alkoxy, C₁₋₄alkylthio, and hydroxy; in addition, pyrimidinyl         is optionally substituted with a single cyano, morpholin-4-yl,         amino, di(C₁₋₄alkyl)amino, or piperazin-1-yl optionally         substituted with 4-C₁₋₄alkyl substituent;     -   iii) pyridinyl optionally substituted with one to two         substituents independently selected from the group consisting of         C₁₋₄alkyl, C₁₋₄alkoxy, C₁₋₄alkylthio, hydroxy, fluoro, chloro,         and cyano; in addition, pyridinyl is optionally substituted with         a single hydroxymethyl, amino, C₁₋₄alkylsulfonyl, or pyridinyl         substituent;         -   wherein the pyridinyl substituent of the R₁-pyridinyl is             optionally independently substituted with one to two             substituents selected from chloro and methyl;     -   and     -   iv) a G-substituent selected from the group consisting of         naphthyl, pyrazolyl, thienyl, benzothiazolyl, quinolinyl,         indolyl, thiazolyl, furanyl, dihydrobenzofuranyl, pyrazinyl,         quinoxalinyl, oxazolyl, pyrrolopyridinyl, benzo[1,3]dioxol-5-yl,         benzo[1,2,5]oxadiazolyl, dibenzothiophenyl,         4H-[1,2,4]oxadiazol-5-on-yl, and benzothiophenyl;     -   wherein G is optionally independently substituted with one to         two C₁₋₄alkyl substituents; -   c) R₁ is selected from the group consisting of     -   i) phenyl optionally substituted with one to two substituents         independently selected from the group consisting of C₁₋₄alkyl,         C₁₋₂alkoxy, hydroxy, chloro, and fluoro; in addition, phenyl is         optionally substituted with a single amino, di(C₁₋₄alkyl)amino,         di(C₁₋₄alkyl)aminocarbonyl, hydroxy(C₁₋₄)alkyl, aminocarbonyl,         C₁₋₄alkylcarbonylamino, cyano, trifluoromethoxy,         C₁₋₄alkylsulfonyl, nitro, trifluoromethyl, or phenyl         substituent;     -   ii) pyrimidinyl optionally substituted with one to two         substituents independently selected from the group consisting of         C₁₋₄alkoxy and C₁₋₄alkylthio; in addition, pyrimidinyl is         optionally substituted with a single cyano, morpholin-4-yl,         di(C₁₋₄alkyl)amino, or piperazin-1-yl optionally substituted         with 4-C₁₋₄alkyl substituent;     -   iii) pyridinyl optionally substituted with one to two         substituents independently selected from the group consisting of         C₁₋₄alkyl, C₁₋₄alkoxy, C₁₋₄alkylthio, hydroxy, fluoro, chloro,         and cyano; in addition, pyridinyl is optionally substituted with         a single hydroxymethyl, amino, C₁₋₄alkylsulfonyl, or pyridinyl         substituent;         -   wherein the pyridinyl substituent of the R₁-pyridinyl is             optionally independently substituted with one to two             substituents selected from chloro and methyl;     -   and     -   iv) a G-substituent selected from the group consisting of         naphthyl, pyrazolyl, thienyl, benzothiazolyl, quinolinyl,         indolyl, thiazolyl, furanyl, dihydrobenzofuranyl, pyrazinyl,         quinoxalinyl, pyrrolopyridinyl, benzo[1,3]dioxol-5-yl,         benzo[1,2,5]oxadiazolyl, dibenzothiophenyl,         4H-[1,2,4]oxadiazol-5-on-yl, and benzothiophenyl;     -   wherein G is optionally substituted with one C₁₋₄alkyl         substituent; -   d) R₁ is selected from the group consisting of     -   i) phenyl optionally substituted with one to two substituents         independently selected from the group consisting of C₁₋₄alkyl,         C₁₋₂alkoxy, hydroxy, and fluoro; in addition, phenyl is         optionally substituted with a single amino, di(C₁₋₄alkyl)amino,         di(C₁₋₄alkyl)aminocarbonyl, hydroxy(C₁₋₄)alkyl, aminocarbonyl,         C₁₋₄alkylcarbonylamino, cyano, trifluoromethoxy,         C₁₋₄alkylsulfonyl, nitro, or trifluoromethyl substituent;     -   ii) pyrimidinyl optionally substituted with one to two         substituents independently selected from the group consisting of         C₁₋₄alkoxy and C₁₋₄alkylthio; in addition, pyrimidinyl is         optionally substituted with a single cyano, morpholin-4-yl,         di(C₁₋₄alkyl)amino, or piperazin-1-yl optionally substituted         with 4-C₁₋₄alkyl substituent;     -   iii) pyridinyl optionally substituted with one to two         substituents independently selected from the group consisting of         C₁₋₄alkyl, C₁₋₄alkoxy, C₁₋₄alkylthio, hydroxy, fluoro, chloro,         and cyano; in addition, pyridinyl is optionally substituted with         a single hydroxymethyl or amino substituent;     -   and     -   iv) a G-substituent selected from the group consisting of         pyrazolyl, thienyl, benzothiazolyl, quinolinyl, indolyl,         thiazolyl, furanyl, dihydrobenzofuranyl, benzo[1,3]dioxol-5-yl,         and benzo[1,2,5]oxadiazolyl;     -   wherein G is optionally independently substituted with one         C₁₋₄alkyl substituent; -   e) R₁ is selected from the group consisting of     -   i) phenyl optionally substituted with a substituent selected         from the group consisting of C₁₋₂alkyl, C₁₋₂alkoxy, hydroxy, and         fluoro; or, phenyl is optionally substituted with one         substituent selected from the group consisting of amino,         di(C₁₋₄alkyl)amino, di(C₁₋₄alkyl)aminocarbonyl, hydroxymethyl,         aminocarbonyl, C₁₋₄alkylcarbonylamino, cyano, trifluoromethoxy,         C₁₋₂alkylsulfonyl, nitro, and trifluoromethyl;     -   ii) pyrimidinyl optionally substituted with one to two         substituents selected from the group consisting of C₁₋₄alkoxy         and C₁₋₄alkylthio; or, pyrimidinyl is optionally substituted         with one substituent selected from the group consisting of         morpholin-4-yl, di(C₁₋₄alkyl)amino, and piperazin-1-y optionally         substituted with 4-methyl;     -   iii) pyridinyl optionally substituted with one to two         substituents selected from the group consisting of C₁₋₄alkyl,         C₁₋₄alkoxy, C₁₋₄alkylthio, hydroxy, fluoro, and chloro; or,         pyridinyl optionally substituted with one substituent selected         from the group consisting of cyano, hydroxymethyl, and amino;     -   and     -   iv) a G-substituent selected from the group consisting of         pyrazolyl, thienyl, benzothiazolyl, quinolinyl, indolyl,         thiazolyl, furanyl, dihydrobenzofuranyl, benzo[1,3]dioxol-5-yl,         and benzo[1,2,5]oxadiazolyl;     -   wherein G is optionally independently substituted with one         C₁₋₄alkyl substituent; -   f) R₂ is     -   (i) phenyl optionally substituted with one to two substituents         independently selected from the group consisting of C₁₋₄alkyl,         C₁₋₄alkoxy, C₁₋₄alkylthio, one to two fluoro substituents,         chloro, and hydroxy; in addition, phenyl is optionally         substituted with a single amino, fluoromethyl, trifluoromethyl,         fluoromethoxy, difluoromethoxy, trifluoromethoxy, formamidino,         aminocarbonyl, di(C₁₋₄)alkylaminocarbonyl,         C₁₋₄alkylcarbonylamino, 2,2,2-trifluoroethoxy, cyano,         C₃₋₇cycloalkylcarbonylamino, hydroxy(C₁₋₄alkyl,         C₁₋₄alkoxy(C₁₋₄)alkyl, C₁₋₄alkoxy-(C₁₋₄)alkoxy,         C₁₋₄alkylcarbonyloxy, C₁₋₄alkylsulfonylamino, C₁₋₄alkylsulfonyl,         pyridinyl(C₁₋₄)alkyl, benzyloxycarbonylamino,         4-methyl-piperazin-1-ylcarbonyl, pyrrolidin-1-ylcarbonyl,         carboxy, piperidin-1-ylcarbonyl, or morpholin-4-ylcarbonyl         substituent;     -   or     -   (ii) heteroaryl selected from the group consisting of         benzothiazolyl, benzooxazolyl, and pyridinyl; wherein heteroaryl         is optionally independently substituted with one to two         C₁₋₄alkyl substituents; -   g) R₂ is     -   (i) phenyl optionally substituted with one to two substituents         independently selected from the group consisting of C₁₋₄alkyl,         C₁₋₂alkoxy, C₁₋₄alkylthio, one to two fluoro substituents,         chloro, and hydroxy; in addition, phenyl is optionally         substituted with a single amino, fluoromethyl, trifluoromethyl,         fluoromethoxy, difluoromethoxy, trifluoromethoxy, formamidino,         aminocarbonyl, C₁₋₄alkylcarbonylamino, C₁₋₄alkylcarbonyloxy,         2,2,2-trifluoroethoxy, benzyloxycarbonylamino,         hydroxy(C₁₋₄)alkyl, or C₁₋₄alkoxy(C₁₋₄)alkyl substituent;     -   or, (ii) heteroaryl selected from the group consisting of         benzothiazolyl and benzooxazolyl; wherein heteroaryl is         optionally independently substituted with one to two C₁₋₄alkyl         substituents; -   h) R₂ is     -   (i) phenyl optionally substituted with one to two substituents         selected from the group consisting of C₁₋₄alkyl, C₁₋₂alkoxy,         C₁₋₄alkylthio, one to two fluoro substituents, chloro, and         hydroxy; in addition, phenyl is optionally substituted with a         single amino, fluoromethoxy, difluoromethoxy, trifluoromethoxy,         formamidino, aminocarbonyl, C₁₋₄alkylcarbonylamino,         C₁₋₄alkylcarbonyloxy, 2,2,2-trifluoroethoxy, or         C₁₋₄alkoxy(C₁₋₄)alkyl substituent;     -   or,     -   (ii) heteroaryl selected from the group consisting of         benzothiazolyl and benzooxazolyl; wherein heteroaryl is         optionally independently substituted with one to two C₁₋₄alkyl         substituents; -   i) R₂ is     -   (i) phenyl optionally substituted with one to two substituents         selected from the group consisting of C₁₋₂alkyl, C₁₋₂alkoxy,         C₁₋₂alkylthio, fluoro, 3-chloro, 4-chloro, and hydroxy; or         phenyl is optionally substituted with one substituent selected         from the group consisting of amino, difluoromethoxy,         trifluoromethoxy, aminocarbonyl, C₁₋₄alkylcarbonylamino,         C₁₋₄alkylcarbonyloxy, and 2,2,2-trifluoroethoxy;     -   or,     -   (ii) heteroaryl selected from the group consisting of         benzothiazolyl and benzooxazolyl; wherein heteroaryl of R₂ is         optionally independently substituted with one to two C₁₋₂alkyl         substituents; -   j) R₂ is     -   (i) phenyl optionally substituted with one to two substituents         selected from the group consisting of C₁₋₂alkyl, C₁₋₂alkoxy,         C₁₋₂alkylthio, one to two fluoro substituents, 3-chloro,         4-chloro, and hydroxy; or, phenyl is optionally substituted with         one substituent selected from the group consisting of amino,         difluoromethoxy, trifluoromethoxy, aminocarbonyl,         C₁₋₄alkylcarbonylamino, C₁₋₄alkylcarbonyloxy, and         2,2,2-trifluoroethoxy;     -   or,     -   (ii) R₂ is a heteroaryl selected from the group consisting of         benzothiazolyl and benzooxazolyl; wherein heteroaryl of R₂ is         optionally independently substituted with one to two C₁₋₂alkyl         substituents; -   k) A-L- is selected from the group consisting of a₁-L₁-; a₂-L₂-;     a₃-L₃-; a₄-L₄-; and a₅-L₅-;     -   L₁ is absent or C₁₋₄alkyl;     -   a₁ is bound through a carbon atom to L₁ and is selected from the         group consisting of     -   i) pyrrolidinyl optionally substituted at carbon with amino,         hydroxy, or one to two fluoro substituents;     -   ii) piperidinyl;     -   and     -   iii) azetidinyl;     -   provided that when L₁ is absent, a₁ is attached to N(R_(a)) via         a carbon atom other than that which is alpha to a nitrogen atom         of a₁;     -   and provided that when a₁ is substituted with a substituent         containing an oxygen or nitrogen radical as a point of         attachment to a₁, the substitution is at a carbon atom other         than that alpha to a nitrogen atom of a₁;     -   L₂ is C₁₋₄alkyl;     -   a₂ is bound through a carbon atom to L₂ and a₂ is morpholinyl;     -   L₃ is methylene;     -   a₃ is imidazolyl optionally independently substituted with one         to two C₁₋₄alkyl substituents;     -   L₄ is (C₂₋₆)alkyl;     -   a₄ is selected from the group consisting of amino and         C₁₋₄alkylamino;     -   provided that a₄ is attached at a carbon atom of (C₂₋₆)alkyl         other than that alpha to N(R_(a));     -   L₅ is absent or C₁₋₄alkyl;     -   a₅ is C₃₋₇cycloalkyl substituted with R_(B); wherein R_(B) is         amino;     -   provided that when R_(B) contains a nitrogen radical as a point         of attachment to C₃₋₇cycloalkyl, the attachment is at a carbon         atom other than that alpha to N(R_(a));     -   or,     -   A-L- is taken with R_(a) and the nitrogen atom to which they are         both attached to form a nitrogen-bound heterocyclyl selected         from the group consisting of     -   i) pyrrolidin-1-yl wherein pyrrolidin-1-yl is optionally         substituted with C₁₋₄alkyl, amino, or aminomethyl;     -   ii) piperazin-1-yl optionally substituted with 4-C₁₋₄alkyl; and         wherein piperazin-1-yl is optionally independently substituted         at carbon with one to two C₁₋₄alkyl substituents, 2-oxo, or         3-oxo;     -   iii) piperidin-1-yl optionally substituted with one to two         C₁₋₄alkyl substituents or amino;     -   iv) azetidin-1-yl optionally substituted with 3-amino or         3-aminomethyl;     -   v) [1,4]diazepan-1-yl; and     -   vi) 3,6-diazoabicyclo[3.1.1]hept-3-yl; -   l) A-L- is selected from the group consisting of a₁-L₁-; a₂-L₂-;     a₃-L₃-; a₄-L₄-; and a₅-L₅-;     -   L₁ is absent or C₁₋₂alkyl;     -   a₁ is bound through a carbon atom to L₁ and is selected from the         group consisting of     -   i) pyrrolidinyl optionally substituted at carbon with hydroxy or         one to two fluoro substituents;     -   ii) piperidin-3-yl;     -   and     -   iii) azetidinyl;     -   provided that when L₁ is absent, a₁ is attached to N(R_(a)) via         a carbon atom other than that which is alpha to a nitrogen atom         of a₁;     -   and provided that when a₁ is substituted with a substituent         containing an oxygen or nitrogen radical as a point of         attachment to a₁, the substitution is at a carbon atom other         than that alpha to a nitrogen atom of a₁;     -   L₂ is C₁₋₂alkyl;     -   a₂ is bound through a carbon atom to L₂ and a₂ is morpholinyl;     -   L₃ is methylene;     -   a₃ is imidazolyl optionally independently substituted with one         to two C₁₋₂alkyl substituents;     -   L₄ is (C₂₋₄)alkyl;     -   a₄ is selected from the group consisting of amino and         C₁₋₄alkylamino;     -   provided that a₄ is attached at a carbon atom other than that         alpha to N(R_(a));     -   L₅ is absent or C₁₋₄alkyl;     -   a₅ is C₄₋₆cycloalkyl substituted with R_(B); wherein R_(B) is         amino;     -   provided that when R_(B) contains a nitrogen radical as the         point of attachment to C₅₋₆cycloalkyl, the attachment is at a         carbon atom other than that alpha to N(R_(a));     -   or,     -   A-L- is taken with R_(a) and the nitrogen atom to which they are         both attached to form a nitrogen-bound heterocyclyl selected         from the group consisting of     -   i) pyrrolidin-1-yl optionally substituted with amino or         aminomethyl;     -   ii) piperazin-1-yl optionally substituted with 4-C₁₋₄alkyl; and         wherein piperazin-1-yl is optionally independently substituted         at carbon with one to two C₁₋₄alkyl substituents;     -   iii) piperidin-1-yl optionally substituted with amino;     -   iv) azetidin-1-yl optionally substituted with 3-aminomethyl; and     -   v) [1,4]diazepan-1-yl;     -   provided that the position of a substituent containing a         nitrogen radical as a point of attachment to the nitrogen-bound         heterocyclyl is at a carbon atom other than that alpha to a         heterocyclyl nitrogen atom; -   m) A-L- is selected from the group consisting of a₁-L₁-; a₂-L₂-;     a₃-L₃-, a₄-L₄-; and a₅-L₅-;     -   L₁ is absent or C₁₋₂alkyl;     -   a₁ is bound through a carbon atom to L₁ and is selected from the         group consisting of     -   i) pyrrolidinyl optionally substituted at carbon with hydroxy or         one to two fluoro substituents;     -   and     -   ii) piperidin-3-yl     -   provided that when L₁ is absent, a₁ is attached to N(R_(a)) via         a carbon atom other than that which is alpha to a nitrogen atom         of a₁;     -   and provided that when a₁ is substituted with a substituent         containing an oxygen or nitrogen radical as a point of         attachment to a₁, the substitution is at a carbon atom other         than that alpha to a nitrogen atom of a₁;     -   L₂ is C₁₋₂alkyl;     -   a₂ is bound through a carbon atom to L₂ and a₂ is morpholinyl;     -   L₃ is methylene;     -   a₃ is imidazolyl optionally substituted with one to two methyl         substituents;     -   L₄ is (C₂₋₃)alkyl;     -   a₄ is amino, provided that a₄ is attached at a carbon atom other         than that alpha to N(R_(a)); L₂ is methylene;     -   L₅ is absent or C₁₋₂alkyl;     -   a₅ is C₄₋₆cycloalkyl substituted with R_(B); wherein R_(B) is         amino;     -   provided that when R_(B) contains a nitrogen radical as the         point of attachment to C₅₋₆cycloalkyl, the attachment is at a         carbon atom other than that alpha to N(R_(a));     -   or,     -   A-L- is taken with R_(a) and the nitrogen atom to which they are         both attached to form a nitrogen-bound heterocyclyl selected         from the group consisting of     -   i) pyrrolidin-1-yl optionally substituted with amino;     -   ii) piperazin-1-yl optionally independently substituted at         carbon with one to two C₁₋₄alkyl substituents;     -   iii) piperidin-1-yl optionally substituted with amino;     -   and     -   iv) [1,4]diazepan-1-yl;     -   provided that the position of a substituent containing an         nitrogen radical as a point of attachment to the nitrogen-bound         heterocyclyl is at a carbon atom other than that alpha to the         heterocyclyl nitrogen atom -   n) A-L- is selected from the group consisting of a₁-L₁-; a₂-L₂-;     a₃-L₃-, a₄-L₄-; and a₅-L₅-; -   L₁ is absent or C₁₋₂alkyl; -   a₁ is bound through a carbon atom to L₁ and is selected from the     group consisting of -   i) pyrrolidinyl optionally substituted at carbon with hydroxy or one     to two fluoro substituents;     -   and     -   ii) piperidin-3-yl     -   provided that when L₁ is absent, a₁ is attached to N(R_(a)) via         a carbon atom other than that which is alpha to a nitrogen atom         of a₁;     -   and provided that when a₁ is substituted with a substituent         containing an oxygen or nitrogen radical as a point of         attachment to a₁, the substitution is at a carbon atom other         than that alpha to a nitrogen atom of a₁;     -   L₂ is methylene;     -   a₂ is bound through a carbon atom to L₂ and a₂ is morpholinyl;     -   L₃ is methylene;     -   a₃ is imidazolyl optionally substituted with one to two methyl         substituents;     -   L₄ is (C₂₋₃)alkyl;     -   a₄ is amino, provided that a₄ is attached at a carbon atom other         than that alpha to N(R_(a));     -   L₅ is absent or C₁₋₂alkyl;     -   a₅ is C₄₋₆cycloalkyl substituted with R_(B); wherein R_(B) is         amino;     -   provided that when R_(B) contains a nitrogen radical as the         point of attachment to C₅₋₆cycloalkyl, the attachment is at a         carbon atom other than that alpha to N(R_(a));     -   or,     -   A-L- is taken with R_(a) and the nitrogen atom to which they are         both attached to form a nitrogen-bound heterocyclyl selected         from the group consisting of     -   i) pyrrolidin-1-yl optionally substituted with amino;     -   ii) piperazin-1-yl optionally independently substituted at         carbon with one to two C₁₋₂alkyl substituents;     -   iii) piperidin-1-yl optionally substituted with amino;     -   and     -   iv) [1,4]diazepan-1-yl;     -   provided that the position of a substituent containing an         nitrogen radical as a point of attachment to the nitrogen-bound         heterocyclyl is at a carbon atom other than that alpha to the         heterocyclyl nitrogen atom; -   o) R_(a) is hydrogen; -   provided that a compound of Formula (I) is other than a compound     selected from the group consisting of -   a compound wherein R₁ is 4-fluoro-phenyl, R₂ is 4-methoxy-phenyl,     A-L- is a₁-L₁, a₁ is (S)-pyrrolidin-2-yl, L₁ is methyl, R_(a) is H,     and X is O; -   a compound wherein R₁ is pyrimidin-5-yl, R₂ is 4-methoxy-phenyl,     A-L- is a₂-L₂, a₂ is (S)-morpholin-3-yl, L₂ is methyl, R_(a) is H,     and X is O; a compound wherein R₁ is 5-fluoro-pyridin-3-yl, R₂ is     4-(piperidin-1-ylcarbonyl)-phenyl, A-L- is a₁-L₁, a₁ is     (S)-pyrrolidin-2-yl, L₁ is methyl, R_(a) is H, and X is O; -   a compound wherein R₁ is 5-fluoro-pyridin-3-yl, R₂ is     4-(4-methyl-piperazin-1-ylcarbonyl)-phenyl, A-L- is a₁-L₁, a₁ is     (S)-pyrrolidin-2-yl, L₁ is methyl, R_(a) is H, and X is O; -   a compound wherein R₁ is 5-cyano-pyridin-3-yl, R₂ is     2-methyl-phenyl, A-L- is a₁-L₁, a₁ is (S)-pyrrolidin-2-yl, L₁ is     methyl, R_(a) is H, and X is O; -   a compound wherein R₁ is pyridin-3-yl, R₂ is 4-methoxy-phenyl, A-L-     is a₅-L₅, a₅ is cyclohexyl, L₅ is absent, R_(B) is 2-amino, R_(a) is     H, and X is O; -   and -   a compound wherein R₁ is 5-fluoro-pyridin-3-yl, R₂ is     4-diethylaminocarbonyl-phenyl, A-L- is a₁-L₁, a₁ is     (S)-pyrrolidin-2-yl, L₁ is methyl, R_(a) is H, and X is O;     -   and any combination of embodiments a) through o) above, provided         that it is understood that combinations in which different         embodiments of the same substituent would be combined are         excluded;     -   and enantiomers, diastereomers, solvates, and pharmaceutically         acceptable salts thereof.

A further embodiment of the present invention is directed to a compound of Formula (I)

-   wherein -   R₁ is selected from the group consisting of -   i) phenyl optionally substituted with one to two substituents     independently selected from the group consisting of C₁₋₄alkyl,     C₁₋₄alkoxy, hydroxy, chloro, and fluoro; in addition, phenyl is     optionally substituted with a single amino, di(C₁₋₄alkyl)amino,     di(C₁₋₄alkyl)aminocarbonyl, hydroxy(C₁₋₄alkyl, aminocarbonyl,     C₁₋₄alkylcarbonylamino, cyano, trifluoromethoxy, C₁₋₄alkylsulfonyl,     nitro, trifluoromethyl, or phenyl substituent; -   ii) pyrimidinyl optionally substituted with one to two substituents     independently selected from the group consisting of C₁₋₄alkoxy,     C₁₋₄alkylthio, and hydroxy; in addition, pyrimidinyl is optionally     substituted with a single cyano, morpholin-4-yl, amino,     di(C₁₋₄alkyl)amino, or piperazin-1-yl optionally substituted with     4-C₁₋₄alkyl substituent; -   iii) pyridinyl optionally substituted with one to two substituents     independently selected from the group consisting of C₁₋₄alkyl,     C₁₋₄alkoxy, C₁₋₄alkylthio, hydroxy, fluoro, chloro, and cyano; in     addition, pyridinyl is optionally substituted with a single     hydroxymethyl, amino, aminocarbonyl, C₁₋₄alkylsulfonyl, or pyridinyl     substituent;     -   wherein the pyridinyl substituent of the R₁-pyridinyl is         optionally independently substituted with one to two         substituents selected from chloro and methyl; -   and -   iv) a G-substituent selected from the group consisting of naphthyl,     pyrazolyl, thienyl, benzothiazolyl, quinolinyl, indolyl, thiazolyl,     furanyl, dihydrobenzofuranyl, pyrazinyl, quinoxalinyl, oxazolyl,     pyrrolopyridinyl, benzo[1,3]dioxol-5-yl, benzo[1,2,5]oxadiazolyl,     dibenzothiophenyl, 4H-[1,2,4]oxadiazol-5-on-yl, and benzothiophenyl;     -   wherein G is optionally independently substituted with one to         two substituents selected from the group consisting of         C₁₋₄alkyl, fluoro, and chloro; -   R₂ is -   (i) phenyl optionally substituted with one to two substituents     independently selected from the group consisting of C₁₋₄alkyl,     C₁₋₄alkoxy, C₁₋₄alkylthio, one to two fluoro substituents, chloro,     and hydroxy; in addition, phenyl is optionally substituted with     amino, fluoromethyl, trifluoromethyl, fluoromethoxy,     difluoromethoxy, trifluoromethoxy, formamidino, aminocarbonyl,     di(C₁₋₄)alkylaminocarbonyl, C₁₋₄alkylcarbonylamino,     2,2,2-trifluoroethoxy, cyano, C₃₋₇cycloalkylcarbonylamino,     hydroxy(C₁₋₄alkyl, C₁₋₄alkoxy(C₁₋₄)alkyl, C₁₋₄alkoxy-(C₁₋₄)alkoxy,     C₁₋₄alkylcarbonyloxy, C₁₋₄alkylsulfonylamino, C₁₋₄alkylsulfonyl,     pyridinyl(C₁₋₄alkyl, benzyloxycarbonylamino,     4-methyl-piperazin-1-ylcarbonyl, pyrrolidin-1-ylcarbonyl, carboxy,     piperidin-1-ylcarbonyl, or morpholin-4-ylcarbonyl; -   or, -   (ii) heteroaryl selected from the group consisting of     benzothiazolyl, benzooxazolyl, and pyridinyl; wherein heteroaryl is     optionally independently substituted with one to two C₁₋₄alkyl     substituents; -   A-L- is selected from the group consisting of a₁-L₁-; a₂-L₂-;     a₃-L₃-; a₄-L₄-; and a₅-L₅-; -   L₁ is absent or C₁₋₄alkyl; -   a₁ is bound through a carbon atom to L₁ and is selected from the     group consisting of -   i) pyrrolidinyl optionally substituted at carbon with amino,     hydroxy, or one to two fluoro substituents; -   ii) piperidinyl; -   and -   iii) azetidinyl; -   provided that when L₁ is absent, a₁ is attached to N(R_(a)) via a     carbon atom other than that which is alpha to a nitrogen atom of a₁; -   and provided that when a₁ is substituted with a substituent     containing an oxygen or nitrogen radical as a point of attachment to     a₁, the substitution is at a carbon atom other than that alpha to a     nitrogen atom of a₁; -   L₂ is C₁₋₄alkyl; -   a₂ is bound through a carbon atom to L₂ and a₂ is morpholinyl; -   L₃ is methylene; -   a₃ is imidazolyl optionally independently substituted with one to     two C₁₋₄alkyl substituents; -   L₄ is (C₂₋₆)alkyl; -   a₄ is selected from the group consisting of amino and     C₁₋₄alkylamino; -   provided that a₄ is attached at a carbon atom of (C₂₋₆)alkyl other     than that alpha to N(R_(a)); -   L₅ is absent or C₁₋₄alkyl; -   a₅ is C₃₋₇cycloalkyl substituted with R_(B); wherein R_(B) is amino; -   provided that when R_(B) contains a nitrogen radical as a point of     attachment to C₃₋₇cycloalkyl, the attachment is at a carbon atom     other than that alpha to N(R_(a)); -   or, -   A-L- is taken with R_(a) and the nitrogen atom to which they are     both attached to form a nitrogen-bound heterocyclyl selected from     the group consisting of -   i) pyrrolidin-1-yl wherein pyrrolidin-1-yl is optionally substituted     with C₁₋₄alkyl, amino, or aminomethyl; -   ii) piperazin-1-yl optionally substituted with 4-C₁₋₄alkyl; and     wherein piperazin-1-yl is optionally independently substituted at     carbon with one to two C₁₋₄alkyl substituents, 2-oxo, or 3-oxo; -   iii) piperidin-1-yl optionally substituted with one to two C₁₋₄alkyl     substituents or amino; -   iv) azetidin-1-yl optionally substituted with 3-amino or     3-aminomethyl; -   v) [1,4]diazepan-1-yl; and -   vi) 3,6-diazoabicyclo[3.1.1]hept-3-yl; -   R_(a) is hydrogen or methylcarbonyl; -   provided that a compound of Formula (I) is other than a compound     selected from the group consisting of -   a compound wherein R₁ is 4-fluoro-phenyl, R₂ is 4-methoxy-phenyl,     A-L- is a₁-L₁, a₁ is (S)-pyrrolidin-2-yl, L₁ is methyl, R_(a) is H,     and X is O; -   a compound wherein R₁ is pyrimidin-5-yl, R₂ is 4-methoxy-phenyl,     A-L- is a₂-L₂, a₂ is (S)-morpholin-3-yl, L₂ is methyl, R_(a) is H,     and X is O; -   a compound wherein R₁ is 5-fluoro-pyridin-3-yl, R₂ is     4-(piperidin-1-ylcarbonyl)-phenyl, A-L- is a₁-L₁, a₁ is     (S)-pyrrolidin-2-yl, L₁ is methyl, R_(a) is H, and X is O; -   a compound wherein R₁ is 5-fluoro-pyridin-3-yl, R₂ is     4-(4-methyl-piperazin-1-ylcarbonyl)-phenyl, A-L- is a₁-L₁, a₁ is     (S)-pyrrolidin-2-yl, L₁ is methyl, R_(a) is H, and X is O; -   a compound wherein R₁ is 5-cyano-pyridin-3-yl, R₂ is     2-methyl-phenyl, A-L- is a₁-L₁, a₁ is (S)-pyrrolidin-2-yl, L₁ is     methyl, R_(a) is H, and X is O; and -   a compound wherein R₁ is pyridin-3-yl, R₂ is 4-methoxy-phenyl, A-L-     is a₅-L₅, a₅ is cyclohexyl, L₅ is absent, R_(B) is 2-amino, R_(a) is     H, and X is O; -   and enantiomers, diastereomers, solvates, and pharmaceutically     acceptable salts thereof.

A further embodiment of the present invention is directed to a compound of Formula (I)

-   wherein -   R₁ is selected from the group consisting of -   i) phenyl optionally substituted with one to two substituents     independently selected from the group consisting of C₁₋₄alkyl,     C₁₋₄alkoxy, hydroxy, chloro, and fluoro; in addition, phenyl is     optionally substituted with a single amino, di(C₁₋₄alkyl)amino,     di(C₁₋₄alkyl)aminocarbonyl, hydroxy(C₁₋₄alkyl, aminocarbonyl,     C₁₋₄alkylcarbonylamino, cyano, trifluoromethoxy, C₁₋₄alkylsulfonyl,     nitro, trifluoromethyl, or phenyl substituent; -   ii) pyrimidinyl optionally substituted with one to two substituents     independently selected from the group consisting of C₁₋₄alkoxy,     C₁₋₄alkylthio, and hydroxy; in addition, pyrimidinyl is optionally     substituted with a single cyano, morpholin-4-yl, amino,     di(C₁₋₄alkyl)amino, or piperazin-1-yl optionally substituted with     4-C₁₋₄alkyl substituent; -   iii) pyridinyl optionally substituted with one to two substituents     independently selected from the group consisting of C₁₋₄alkyl,     C₁₋₄alkoxy, C₁₋₄alkylthio, hydroxy, fluoro, chloro, and cyano; in     addition, pyridinyl is optionally substituted with a single     hydroxymethyl, amino, C₁₋₄alkylsulfonyl, or pyridinyl substituent;     -   wherein the pyridinyl substituent of the R₁-pyridinyl is         optionally independently substituted with one to two         substituents selected from chloro and methyl; -   and -   iv) a G-substituent selected from the group consisting of naphthyl,     pyrazolyl, thienyl, benzothiazolyl, quinolinyl, indolyl, thiazolyl,     furanyl, dihydrobenzofuranyl, pyrazinyl, quinoxalinyl, oxazolyl,     pyrrolopyridinyl, benzo[1,3]dioxol-5-yl, benzo[1,2,5]oxadiazolyl,     dibenzothiophenyl, 4H-[1,2,4]oxadiazol-5-on-yl, and benzothiophenyl;     wherein G is optionally independently substituted with one to two     C₁₋₄alkyl substituents; -   R₂ is -   (i) phenyl optionally substituted with one to two substituents     independently selected from the group consisting of C₁₋₄alkyl,     C₁₋₂alkoxy, C₁₋₄alkylthio, one to two fluoro substituents, chloro,     and hydroxy; in addition, phenyl is optionally substituted with     amino, fluoromethyl, trifluoromethyl, fluoromethoxy,     difluoromethoxy, trifluoromethoxy, formamidino, aminocarbonyl,     C₁₋₄alkylcarbonylamino, C₁₋₄alkylcarbonyloxy, 2,2,2-trifluoroethoxy,     benzyloxycarbonylamino, hydroxy(C₁₋₄)alkyl, or     C₁₋₄alkoxy(C₁₋₄)alkyl; -   or, -   (ii) heteroaryl selected from the group consisting of benzothiazolyl     and benzooxazolyl; wherein heteroaryl is optionally independently     substituted with one to two C₁₋₄alkyl substituents; -   A-L- is selected from the group consisting of a₁-L₁-; a₂-L₂-;     a₃-L₃-; a₄-L₄-; and a₅-L₅-; -   L₁ is absent or C₁₋₂alkyl; -   a₁ is bound through a carbon atom to L₁ and is selected from the     group consisting of -   i) pyrrolidinyl optionally substituted at carbon with hydroxy or one     to two fluoro substituents; -   ii) piperidin-3-yl; -   and -   iii) azetidinyl; -   provided that when L₁ is absent, a₁ is attached to N(R_(a)) via a     carbon atom other than that which is alpha to a nitrogen atom of a₁; -   and provided that when a₁ is substituted with a substituent     containing an oxygen or nitrogen radical as a point of attachment to     a₁, the substitution is at a carbon atom other than that alpha to a     nitrogen atom of a₁; -   L₂ is C₁₋₂alkyl; -   a₂ is bound through a carbon atom to L₂ and a₂ is morpholinyl; -   L₃ is methylene; -   a₃ is imidazolyl optionally independently substituted with one to     two C₁₋₂alkyl substituents; -   L₄ is (C₂₋₄)alkyl; -   a₄ is selected from the group consisting of amino and     C₁₋₄alkylamino; -   provided that a₄ is attached at a carbon atom other than that alpha     to N(R_(a)); -   L₅ is absent or C₁₋₄alkyl; -   a₅ is C₄₋₆cycloalkyl substituted with R_(B); wherein R_(B) is amino; -   provided that when R_(B) contains a nitrogen radical as the point of     attachment to C₅₋₆cycloalkyl, the attachment is at a carbon atom     other than that alpha to N(R_(a)); -   or, -   A-L- is taken with R_(a) and the nitrogen atom to which they are     both attached to form a nitrogen-bound heterocyclyl selected from     the group consisting of -   i) pyrrolidin-1-yl optionally substituted with amino or aminomethyl; -   ii) piperazin-1-yl optionally substituted with 4-C₁₋₄alkyl; and     wherein piperazin-1-yl is optionally independently substituted at     carbon with one to two C₁₋₄alkyl substituents; -   iii) piperidin-1-yl optionally substituted with amino; -   iv) azetidin-1-yl optionally substituted with 3-aminomethyl; and -   v) [1,4]diazepan-1-yl;     -   provided that the position of a substituent containing a         nitrogen radical as a point of attachment to the nitrogen-bound         heterocyclyl is at a carbon atom other than that alpha to a         heterocyclyl nitrogen atom; -   R_(a) is hydrogen; -   provided that a compound of Formula (I) is other than a compound     selected from the group consisting of -   a compound wherein R₁ is 4-fluoro-phenyl, R₂ is 4-methoxy-phenyl,     A-L- is a₁-L₁, a₁ is (S)-pyrrolidin-2-yl, L₁ is methyl, R_(a) is H,     and X is O; -   a compound wherein R₁ is pyrimidin-5-yl, R₂ is 4-methoxy-phenyl,     A-L- is a₂-L₂, a₂ is (S)-morpholin-3-yl, L₂ is methyl, R_(a) is H,     and X is O; -   a compound wherein R₁ is 5-cyano-pyridin-3-yl, R₂ is     2-methyl-phenyl, A-L- is a₁-L₁, a₁ is (S)-pyrrolidin-2-yl, L₁ is     methyl, R_(a) is H, and X is O; -   and -   a compound wherein R₁ is pyridin-3-yl, R₂ is 4-methoxy-phenyl, A-L-     is a₅-L₅, a₅ is cyclohexyl, L₅ is absent, R_(B) is 2-amino, R_(a) is     H, and X is O. -   and enantiomers, diastereomers, solvates, and pharmaceutically     acceptable salts thereof.

A further embodiment of the present invention is directed to a compound of Formula (I)

-   wherein -   R₁ is selected from the group consisting of -   i) phenyl optionally substituted with one to two substituents     independently selected from the group consisting of C₁₋₄alkyl,     C₁₋₂alkoxy, hydroxy, chloro, and fluoro; in addition, phenyl is     optionally substituted with a single amino, di(C₁₋₄alkyl)amino,     di(C₁₋₄alkyl)aminocarbonyl, hydroxy(C₁₋₄alkyl, aminocarbonyl,     C₁₋₄alkylcarbonylamino, cyano, trifluoromethoxy, C₁₋₄alkylsulfonyl,     nitro, trifluoromethyl, or phenyl substituent; -   ii) pyrimidinyl optionally substituted with one to two substituents     independently selected from the group consisting of C₁₋₄alkoxy and     C₁₋₄alkylthio; in addition, pyrimidinyl is optionally substituted     with a single cyano, morpholin-4-yl, di(C₁₋₄alkyl)amino, or     piperazin-1-yl optionally substituted with 4-C₁₋₄alkyl substituent; -   iii) pyridinyl optionally substituted with one to two substituents     independently selected from the group consisting of C₁₋₄alkyl,     C₁₋₄alkoxy, C₁₋₄alkylthio, hydroxy, fluoro, chloro, and cyano; in     addition, pyridinyl is optionally substituted with a single     hydroxymethyl, amino, C₁₋₄alkylsulfonyl, or pyridinyl substituent;     -   wherein the pyridinyl substituent of the R₁-pyridinyl is         optionally independently substituted with one to two         substituents selected from chloro and methyl; -   and -   iv) a G-substituent selected from the group consisting of naphthyl,     pyrazolyl, thienyl, benzothiazolyl, quinolinyl, indolyl, thiazolyl,     furanyl, dihydrobenzofuranyl, pyrazinyl, quinoxalinyl,     pyrrolopyridinyl, benzo[1,3]dioxol-5-yl, benzo[1,2,5]oxadiazolyl,     dibenzothiophenyl, 4H-[1,2,4]oxadiazol-5-on-yl, and benzothiophenyl; -   wherein G is optionally substituted with one C₁₋₄alkyl substituent; -   R₂ is -   (i) phenyl optionally substituted with one to two substituents     selected from the group consisting of C₁₋₄alkyl, C₁₋₂alkoxy,     C₁₋₄alkylthio, one to two fluoro substituents, chloro, and hydroxy;     in addition, phenyl is optionally substituted with a single amino,     fluoromethoxy, difluoromethoxy, trifluoromethoxy, formamidino,     aminocarbonyl, C₁₋₄alkylcarbonylamino, C₁₋₄alkylcarbonyloxy,     2,2,2-trifluoroethoxy, or C₁₋₄alkoxy(C₁₋₄)alkyl substituent; -   or, -   (ii) heteroaryl selected from the group consisting of benzothiazolyl     and benzooxazolyl; wherein heteroaryl is optionally independently     substituted with one to two C₁₋₄alkyl substituents; -   A-L- is selected from the group consisting of a₁-L₁-; a₂-L₂-;     a₃-L₃-; a₄-L₄-; and a₅-L₅-; -   L₁ is absent or C₁₋₂alkyl; -   a₁ is bound through a carbon atom to L₁ and is -   i) pyrrolidinyl optionally substituted at carbon with hydroxy or one     to two fluoro substituents; -   ii) piperidin-3-yl -   or -   iii) azetidinyl; -   provided that when L₁ is absent, a₁ is attached to N(R_(a)) via a     carbon atom other than that which is alpha to a nitrogen atom of a₁; -   and provided that when a₁ is substituted with a substituent     containing a nitrogen radical as a point of attachment to a₁, the     substitution is at a carbon atom other than that alpha to a nitrogen     atom of a₁; -   L₂ is methylene; -   a₂ is bound through a carbon atom to L₂ and a₂ is morpholinyl; -   L₃ is methylene; -   a₃ is imidazolyl optionally independently substituted with one to     two C₁₋₄alkyl substituents; -   L₄ is (C₂₋₃)alkyl; -   a₄ is amino, provided that a₄ is attached at a carbon atom other     than that alpha to N(R_(a)); -   L₅ is absent or C₁₋₂alkyl; -   a₅ is C₄₋₆cycloalkyl substituted with R_(B); wherein R_(B) is amino; -   provided that when R_(B) contains a nitrogen radical as the point of     attachment to C₅₋₆cycloalkyl, the attachment is at a carbon atom     other than that alpha to N(R_(a)); -   or, -   A-L- is taken with R_(a) and the nitrogen atom to which they are     both attached to form a nitrogen-bound heterocyclyl selected from     the group consisting of -   i) pyrrolidin-1-yl optionally substituted with amino or aminomethyl; -   ii) piperazin-1-yl optionally independently substituted at carbon     with one to two C₁₋₄alkyl substituents; -   iii) piperidin-1-yl optionally substituted with amino; -   iv) azetidin-1-yl optionally substituted with 3-aminomethyl; -   and -   v) [1,4]diazepan-1-yl; -   provided that the position of a substituent containing an nitrogen     radical as a point of attachment to the nitrogen-bound heterocyclyl     is at a carbon atom other than that alpha to the heterocyclyl     nitrogen atom; -   R_(a) is hydrogen; -   provided that a compound of Formula (I) is other than a compound     selected from the group consisting of -   a compound wherein R₁ is 4-fluoro-phenyl, R₂ is 4-methoxy-phenyl,     A-L- is a₁-L₁, a₁ is (S)-pyrrolidin-2-yl, L₁ is methyl, R_(a) is H,     and X is O; -   a compound wherein R₁ is pyrimidin-5-yl, R₂ is 4-methoxy-phenyl,     A-L- is a₂-L₂, a₂ is (S)-morpholin-3-yl, L₂ is methyl, R_(a) is H,     and X is O; -   a compound wherein R₁ is 5-cyano-pyridin-3-yl, R₂ is     2-methyl-phenyl, A-L- is a₁-L₁, a₁ is (S)-pyrrolidin-2-yl, L₁ is     methyl, R_(a) is H, and X is O; -   and -   a compound wherein R₁ is pyridin-3-yl, R₂ is 4-methoxy-phenyl, A-L-     is a₅-L₅, a₅ is cyclohexyl, L₅ is absent, R_(B) is 2-amino, R_(a) is     H, and X is O; -   and enantiomers, diastereomers, solvates, and pharmaceutically     acceptable salts thereof.

A further embodiment of the present invention is directed to a compound of Formula (I)

-   wherein -   R₁ is selected from the group consisting of -   i) phenyl optionally substituted with one to two substituents     independently selected from the group consisting of C₁₋₄alkyl,     C₁₋₂alkoxy, hydroxy, and fluoro; in addition, phenyl is optionally     substituted with a single amino, di(C₁₋₄alkyl)amino,     di(C₁₋₄alkyl)aminocarbonyl, hydroxy(C₁₋₄)alkyl, aminocarbonyl,     C₁₋₄alkylcarbonylamino, cyano, trifluoromethoxy, C₁₋₄alkylsulfonyl,     nitro, or trifluoromethyl substituent; -   ii) pyrimidinyl optionally substituted with one to two substituents     independently selected from the group consisting of C₁₋₄alkoxy and     C₁₋₄alkylthio; in addition, pyrimidinyl is optionally substituted     with a single cyano, morpholin-4-yl, di(C₁₋₄alkyl)amino, or     piperazin-1-yl optionally substituted with 4-C₁₋₄alkyl substituent; -   iii) pyridinyl optionally substituted with one to two substituents     independently selected form the group consisting of C₁₋₄alkyl,     C₁₋₄alkoxy, C₁₋₄alkylthio, hydroxy, fluoro, chloro, and cyano; in     addition, pyridinyl is optionally substituted with hydroxymethyl or     amino; -   and -   iv) a G-substituent selected from the group consisting of pyrazolyl,     thienyl, benzothiazolyl, quinolinyl, indolyl, thiazolyl, furanyl,     dihydrobenzofuranyl, benzo[1,3]dioxol-5-yl, and     benzo[1,2,5]oxadiazolyl; -   wherein G is optionally independently substituted with one C₁₋₄alkyl     substituent; -   R₂ is -   (i) phenyl optionally substituted with one to two substituents     selected from the group consisting of C₁₋₂alkyl, C₁₋₂alkoxy,     C₁₋₂alkylthio, fluoro, 3-chloro, 4-chloro, and hydroxy; or phenyl is     optionally substituted with one substituent selected from the group     consisting of amino, difluoromethoxy, trifluoromethoxy,     aminocarbonyl, C₁₋₄alkylcarbonylamino, C₁₋₄alkylcarbonyloxy, and     2,2,2-trifluoroethoxy; -   or, -   (ii) heteroaryl selected from the group consisting of benzothiazolyl     and benzooxazolyl; wherein heteroaryl of R₂ is optionally     independently substituted with one to two C₁₋₂alkyl substituents; -   A-L- is selected from the group consisting of a₁-L₁-; a₂-L₂-;     a₃-L₃-, a₄-L₄-; and a₅-L₅-; -   L₁ is absent or C₁₋₂alkyl; -   a₁ is bound through a carbon atom to L₁ and is -   i) pyrrolidinyl optionally substituted at carbon with hydroxy or one     to two fluoro substituents; -   or -   ii) piperidin-3-yl; -   provided that when L₁ is absent, a₁ is attached to N(R_(a)) via a     carbon atom other than that which is alpha to a nitrogen atom of a₁; -   and provided that when a₁ is substituted with a substituent     containing an oxygen or nitrogen radical as a point of attachment to     a₁, the substitution is at a carbon atom other than that alpha to a     nitrogen atom of a₁; -   L₂ is methylene; -   a₂ is bound through a carbon atom to L₂ and a₂ is morpholinyl; -   L₃ is methylene; -   a₃ is imidazolyl optionally substituted with one to two methyl     substituents; -   L₄ is (C₂₋₃)alkyl; -   a₄ is amino, provided that a₄ is attached at a carbon atom other     than that alpha to N(R_(a)); -   L₅ is absent or C₁₋₂alkyl; -   a₅ is C₄₋₆cycloalkyl substituted with R_(B); wherein R_(B) is amino; -   provided that when R_(B) contains a nitrogen radical as the point of     attachment to C₅₋₆cycloalkyl, the attachment is at a carbon atom     other than that alpha to N(R_(a)); -   or, -   A-L- is taken with R_(a) and the nitrogen atom to which they are     both attached to form a nitrogen-bound heterocyclyl selected from     the group consisting of -   i) pyrrolidin-1-yl optionally substituted with amino; -   ii) piperazin-1-yl optionally independently substituted at carbon     with one to two C₁₋₄alkyl substituents; -   iii) piperidin-1-yl optionally substituted with amino; -   and -   iv) [1,4]diazepan-1-yl; -   provided that the position of a substituent containing an nitrogen     radical as a point of attachment to the nitrogen-bound heterocyclyl     is at a carbon atom other than that alpha to the heterocyclyl     nitrogen atom -   R_(a) is hydrogen; -   provided that a compound of Formula (I) is other than a compound     selected from the group consisting of -   a compound wherein R₁ is 4-fluoro-phenyl, R₂ is 4-methoxy-phenyl,     A-L- is a₁-L₁, a₁ is (S)-pyrrolidin-2-yl, L₁ is methyl, R_(a) is H,     and X is O; -   a compound wherein R₁ is pyrimidin-5-yl, R₂ is 4-methoxy-phenyl,     A-L- is a₂-L₂, a₂ is (S)-morpholin-3-yl, L₂ is methyl, R_(a) is H,     and X is O; -   a compound wherein R₁ is 5-cyano-pyridin-3-yl, R₂ is     2-methyl-phenyl, A-L- is a₁-L₁, a₁ is (S)-pyrrolidin-2-yl, L₁ is     methyl, R_(a) is H, and X is O; -   and -   a compound wherein R₁ is pyridin-3-yl, R₂ is 4-methoxy-phenyl, A-L-     is a₅-L₅, a₅ is cyclohexyl, L₅ is absent, R_(B) is 2-amino, R_(a) is     H, and X is O; -   and enantiomers, diastereomers, solvates, and pharmaceutically     acceptable salts thereof.

A further embodiment of the present invention is directed to a compound of Formula (I)

-   wherein -   R₁ is selected from the group consisting of -   i) phenyl optionally substituted with a substituent selected from     the group consisting of C₁₋₂alkyl, C₁₋₂alkoxy, hydroxy, and fluoro;     or, phenyl is optionally substituted with one substituent selected     from the group consisting of amino, di(C₁₋₄alkyl)amino,     di(C₁₋₄alkyl)aminocarbonyl, hydroxymethyl, aminocarbonyl,     C₁₋₄alkylcarbonylamino, cyano, trifluoromethoxy, C₁₋₂alkylsulfonyl,     nitro, and trifluoromethyl; -   ii) pyrimidinyl optionally substituted with one to two substituents     selected from the group consisting of C₁₋₄alkoxy and C₁₋₄alkylthio;     or, pyrimidinyl is optionally substituted with one substituent     selected from the group consisting of morpholin-4-yl,     di(C₁₋₄alkyl)amino, and piperazin-1-yl optionally substituted with     4-methyl; -   iii) pyridinyl optionally substituted with one to two substituents     selected from the group consisting of C₁₋₄alkyl, C₁₋₄alkoxy,     C₁₋₄alkylthio, hydroxy, fluoro, and chloro; or, pyridinyl optionally     substituted with one substituent selected from the group consisting     of cyano, hydroxymethyl, and amino; -   and -   iv) a G-substituent selected from the group consisting of pyrazolyl,     thienyl, benzothiazolyl, quinolinyl, indolyl, thiazolyl, furanyl,     dihydrobenzofuranyl, benzo[1,3]dioxol-5-yl, and     benzo[1,2,5]oxadiazolyl;     -   wherein G is optionally independently substituted with one         C₁₋₄alkyl substituent; -   R₂ is -   (i) phenyl optionally substituted with one to two substituents     selected from the group consisting of C₁₋₂alkyl, C₁₋₂alkoxy,     C₁₋₂alkylthio, one to two fluoro substituents, 3-chloro, 4-chloro,     and hydroxy; or, phenyl is optionally substituted with one     substituent selected from the group consisting of amino,     difluoromethoxy, trifluoromethoxy, aminocarbonyl,     C₁₋₄alkylcarbonylamino, C₁₋₄alkylcarbonyloxy, and     2,2,2-trifluoroethoxy; -   or, -   (ii) heteroaryl selected from the group consisting of benzothiazolyl     and benzooxazolyl; wherein heteroaryl of R₂ is optionally     independently substituted with one to two C₁₋₂alkyl substituents; -   A-L- is selected from the group consisting of a₁-L₁-; a₂-L₂-;     a₃-L₃-, a₄-L₄-; and a₅-L₅-; -   L₁ is absent or C₁₋₂alkyl; -   a₁ is bound through a carbon atom to L₁ and is -   i) pyrrolidinyl optionally substituted at carbon with hydroxy or one     to two fluoro substituents; -   or -   ii) piperidin-3-yl; -   provided that when L₁ is absent, a₁ is attached to N(R_(a)) via a     carbon atom other than that which is alpha to a nitrogen atom of a₁; -   and provided that when a₁ is substituted with a substituent     containing an oxygen or nitrogen radical as a point of attachment to     a₁, the substitution is at a carbon atom other than that alpha to a     nitrogen atom of a₁; -   L₂ is methylene; -   a₂ is bound through a carbon atom to L₂ and a₂ is morpholinyl; -   L₃ is methylene; -   a₃ is imidazolyl optionally substituted with one to two methyl     substituents; -   L₄ is (C₂₋₃)alkyl; -   a₄ is amino, provided that a₄ is attached at a carbon atom other     than that alpha to N(R_(a)); -   L₅ is absent or C₁₋₂alkyl; -   a₅ is C₄₋₆cycloalkyl substituted with R_(B); wherein R_(B) is amino; -   provided that when R_(B) contains a nitrogen radical as the point of     attachment to C₅₋₆cycloalkyl, the attachment is at a carbon atom     other than that alpha to N(R_(a)); -   or, -   A-L- is taken with R_(a) and the nitrogen atom to which they are     both attached to form a nitrogen-bound heterocyclyl selected from     the group consisting of -   i) pyrrolidin-1-yl optionally substituted with amino; -   ii) piperazin-1-yl optionally independently substituted at carbon     with one to two C₁₋₂alkyl substituents; -   iii) piperidin-1-yl optionally substituted with amino; -   and -   iv) [1,4]diazepan-1-yl; -   provided that the position of a substituent containing an nitrogen     radical as a point of attachment to the nitrogen-bound heterocyclyl     is at a carbon atom other than that alpha to the heterocyclyl     nitrogen atom -   R_(a) is hydrogen; -   provided that a compound of Formula (I) is other than a compound     selected from the group consisting of -   a compound wherein R₁ is 4-fluoro-phenyl, R₂ is 4-methoxy-phenyl,     A-L- is a₁-L₁, a₁ is (S)-pyrrolidin-2-yl, L₁ is methyl, R_(a) is H,     and X is O; -   a compound wherein R₁ is pyrimidin-5-yl, R₂ is 4-methoxy-phenyl,     A-L- is a₂-L₂, a₂ is (S)-morpholin-3-yl, L₂ is methyl, R_(a) is H,     and X is O; -   a compound wherein R₁ is 5-cyano-pyridin-3-yl, R₂ is     2-methyl-phenyl, A-L- is a₁-L₁, a₁ is (S)-pyrrolidin-2-yl, L₁ is     methyl, R_(a) is H, and X is O; -   and -   a compound wherein R₁ is pyridin-3-yl, R₂ is 4-methoxy-phenyl, A-L-     is a₅-L₅, a₅ is cyclohexyl, L₅ is absent, R_(B) is 2-amino, R_(a) is     H, and X is O; -   and enantiomers, diastereomers, solvates, and pharmaceutically     acceptable salts thereof.

A further embodiment of the present invention is directed to a compound of Formula (I)

-   selected from the group consisting of: -   a compound of Formula (I) wherein R₁ is 4-methoxy-phenyl, R₂ is     4-methoxy-phenyl, A-L- is a₁-L₁, a₁ is pyrrolidin-2-yl, L₁ is     methyl, and R_(a) is H; (2S) -   a compound of Formula (I) wherein R₁ is phenyl, R₂ is     4-methoxy-phenyl, A-L- is a₁-L₁, a₁ is pyrrolidin-2-yl, L₁ is     methyl, and R_(a) is H; (2S) -   a compound of Formula (I) wherein R₁ is 3-methoxy-phenyl, R₂ is     4-methoxy-phenyl, A-L- is a₁-L₁, a₁ is pyrrolidin-2-yl, L₁ is     methyl, and R_(a) is H; (2S) -   a compound of Formula (I) wherein R₁ is 2-methoxy-phenyl, R₂ is     4-methoxy-phenyl, A-L- is a₁-L₁, a₁ is pyrrolidin-2-yl, L₁ is     methyl, and R_(a) is H; (2S) -   a compound of Formula (I) wherein R₁ is naphth-1-yl, R₂ is     4-methoxy-phenyl, A-L- is a₁-L₁, a₁ is pyrrolidin-2-yl, L₁ is     methyl, and R_(a) is H; (2S) -   a compound of Formula (I) wherein R₁ is naphth-2-yl, R₂ is     4-methoxy-phenyl, A-L- is a₁-L₁, a₁ is pyrrolidin-2-yl, L₁ is     methyl, and R_(a) is H; (2S) -   a compound of Formula (I) wherein R₁ is pyridin-4-yl, R₂ is     4-methoxy-phenyl, A-L- is a₁-L₁, a₁ is pyrrolidin-2-yl, L₁ is     methyl, and R_(a) is H; (2S) -   a compound of Formula (I) wherein R₁ is pyridin-3-yl, R₂ is     4-methoxy-phenyl, A-L- is a₁-L₁, a₁ is pyrrolidin-2-yl, L₁ is     methyl, and R_(a) is H; (2S) -   a compound of Formula (I) wherein R₁ is thien-3-yl, R₂ is     4-methoxy-phenyl, A-L- is a₁-L₁, a₁ is pyrrolidin-2-yl, L₁ is     methyl, and R_(a) is H; (2S) -   a compound of Formula (I) wherein R₁ is furan-3-yl, R₂ is     4-methoxy-phenyl, A-L- is a₁-L₁, a₁ is pyrrolidin-2-yl, L₁ is     methyl, and R_(a) is H; (2S) -   a compound of Formula (I) wherein R₁ is pyridin-3-yl, R₂ is     4-trifluoromethoxy-phenyl, A-L- is a₁-L₁, a₁ is pyrrolidin-2-yl, L₁     is methyl, and R_(a) is H; (2S) -   a compound of Formula (I) wherein R₁ is pyridin-3-yl, R₂ is     4-aminocarbonyl-phenyl, A-L- is a₁-L₁, a₁ is pyrrolidin-2-yl, L₁ is     methyl, and R_(a) is H; (2S) -   a compound of Formula (I) wherein R₁ is pyridin-3-yl, R₂ is     4-methylcarbonylamino-phenyl, A-L- is a₁-L₁, a₁ is pyrrolidin-2-yl,     L₁ is methyl, and R_(a) is H; (2S) -   a compound of Formula (I) wherein R₁ is pyridin-3-yl, R₂ is phenyl,     A-L- is a₁-L₁, a₁ is pyrrolidin-2-yl, L₁ is methyl, and R_(a) is H;     (2S) -   a compound of Formula (I) wherein R₁ is 3-hydroxy-phenyl, R₂ is     4-methoxy-phenyl, A-L- is a₁-L₁, a₁ is pyrrolidin-2-yl, L₁ is     methyl, and R_(a) is H; (2S) -   a compound of Formula (I) wherein R₁ is quinolin-5-yl, R₂ is     4-methoxy-phenyl, A-L- is a₁-L₁, a₁ is pyrrolidin-2-yl, L₁ is     methyl, and R_(a) is H; (2S) -   a compound of Formula (I) wherein R₁ is quinolin-8-yl, R₂ is     4-methoxy-phenyl, A-L- is a₁-L₁, a₁ is pyrrolidin-2-yl, L₁ is     methyl, and R_(a) is H; (2S) -   a compound of Formula (I) wherein R₁ is 2-methyl-quinolin-5-yl, R₂     is 4-methoxy-phenyl, A-L- is a₁-L₁, a₁ is pyrrolidin-2-yl, L₁ is     methyl, and R_(a) is H; (2S) -   a compound of Formula (I) wherein R₁ is 4-biphenyl, R₂ is     4-methoxy-phenyl, A-L- is a₁-L₁, a₁ is pyrrolidin-2-yl, L₁ is     methyl, and R_(a) is H; (2S) -   a compound of Formula (I) wherein R₁ is quinolin-3-yl, R₂ is     4-methoxy-phenyl, A-L- is a₁-L₁, a₁ is pyrrolidin-2-yl, L₁ is     methyl, and R_(a) is H; (2S) -   a compound of Formula (I) wherein R₁ is dibenzothiophen-2-yl, R₂ is     4-methoxy-phenyl, A-L- is a₁-L₁, a₁ is pyrrolidin-2-yl, L₁ is     methyl, and R_(a) is H; (2S) -   a compound of Formula (I) wherein R₁ is 6-methoxy-pyridin-3-yl, R₂     is 4-methoxy-phenyl, A-L- is a₁-L₁, a₁ is pyrrolidin-2-yl, L₁ is     methyl, and R_(a) is H; (2S) -   a compound of Formula (I) wherein R₁ is pyrimidin-5-yl, R₂ is     4-methoxy-phenyl, A-L- is a₁-L₁, a₁ is pyrrolidin-2-yl, L₁ is     methyl, and R_(a) is H; (2S) -   a compound of Formula (I) wherein R₁ is 2-fluoro-pyridin-3-yl, R₂ is     4-methoxy-phenyl, A-L- is a₁-L₁, a₁ is pyrrolidin-2-yl, L₁ is     methyl, and R_(a) is H; (2S) -   a compound of Formula (I) wherein R₁ is 6-fluoro-pyridin-3-yl, R₂ is     4-methoxy-phenyl, A-L- is a₁-L₁, a₁ is pyrrolidin-2-yl, L₁ is     methyl, and R_(a) is H; (2S) -   a compound of Formula (I) wherein R₁ is 2-methoxy-pyridin-3-yl, R₂     is 4-methoxy-phenyl, A-L- is a₁-L₁, a₁ is pyrrolidin-2-yl, L₁ is     methyl, and R_(a) is H; (2S) -   a compound of Formula (I) wherein R₁ is     2,6-dihydroxy-pyrimidin-5-yl, R₂ is 4-methoxy-phenyl, A-L- is a₁-L₁,     a₁ is pyrrolidin-2-yl, L₁ is methyl, and R_(a) is H; (2S) -   a compound of Formula (I) wherein R₁ is 3-cyano-phenyl, R₂ is     4-methoxy-phenyl, A-L- is a₁-L₁, a₁ is pyrrolidin-2-yl, L₁ is     methyl, and R_(a) is H; (2S) -   a compound of Formula (I) wherein R₁ is 3-nitro-phenyl, R₂ is     4-methoxy-phenyl, A-L- is a₁-L₁, a₁ is pyrrolidin-2-yl, L₁ is     methyl, and R_(a) is H; (2S) -   a compound of Formula (I) wherein R₁ is 3-aminocarbonyl-phenyl, R₂     is 4-methoxy-phenyl, A-L- is a₁-L₁, a₁ is pyrrolidin-2-yl, L₁ is     methyl, and R_(a) is H; (2S) -   a compound of Formula (I) wherein R₁ is     3-N,N-diethylaminocarbonyl-phenyl, R₂ is 4-methoxy-phenyl, A-L- is     a₁-L₁, a₁ is pyrrolidin-2-yl, L₁ is methyl, and R_(a) is H; (2S) -   a compound of Formula (I) wherein R₁ is 3-methanesulfonyl-phenyl, R₂     is 4-methoxy-phenyl, A-L- is a₁-L₁, a₁ is pyrrolidin-2-yl, L₁ is     methyl, and R_(a) is H; (2S) -   a compound of Formula (I) wherein R₁ is 4-hydroxy-phenyl, R₂ is     4-methoxy-phenyl, A-L- is a₁-L₁, a₁ is pyrrolidin-2-yl, L₁ is     methyl, and R_(a) is H; (2S) -   a compound of Formula (I) wherein R₁ is indol-5-yl, R₂ is     4-methoxy-phenyl, A-L- is a₁-L₁, a₁ is pyrrolidin-2-yl, L₁ is     methyl, and R_(a) is H; (2S) -   a compound of Formula (I) wherein R₁ is     4H-[1,2,4]oxadiazol-5-on-3-yl, R₂ is 4-methoxy-phenyl, A-L- is     a₁-L₁, a₁ is pyrrolidin-2-yl, L₁ is methyl, and R_(a) is H; (2S) -   a compound of Formula (I) wherein R₁ is pyridin-3-yl, R₂ is     4-fluoro-phenyl, A-L- is a₁-L₁, a₁ is pyrrolidin-2-yl, L₁ is methyl,     and R_(a) is H; (2S) -   a compound of Formula (I) wherein R₁ is 6-methoxy-pyridin-3-yl, R₂     is 4-fluoro-phenyl, A-L- is a₁-L₁, a₁ is pyrrolidin-2-yl, L₁ is     methyl, and R_(a) is H; (2S) -   a compound of Formula (I) wherein R₁ is 3-fluoro-phenyl, R₂ is     4-methoxy-phenyl, A-L- is a₁-L₁, a₁ is pyrrolidin-2-yl, L₁ is     methyl, and R_(a) is H; (2S) -   a compound of Formula (I) wherein R₁ is 6-methoxy-pyridin-3-yl, R₂     is 2-methoxy-phenyl, A-L- is a₁-L₁, a₁ is pyrrolidin-2-yl, L₁ is     methyl, and R_(a) is H; (2S) -   a compound of Formula (I) wherein R₁ is pyridin-3-yl, R₂ is     2-methoxy-phenyl, A-L- is a₁-L₁, a₁ is pyrrolidin-2-yl, L₁ is     methyl, and R_(a) is H; (2S) -   a compound of Formula (I) wherein R₁ is 3-diethylamino-phenyl, R₂ is     4-methoxy-phenyl, A-L- is a₁-L₁, a₁ is pyrrolidin-2-yl, L₁ is     methyl, and R_(a) is H; (2S) -   a compound of Formula (I) wherein R₁ is     3-methylcarbonylamino-phenyl, R₂ is 4-methoxy-phenyl, A-L- is a₁-L₁,     a₁ is pyrrolidin-2-yl, L₁ is methyl, and R_(a) is H; (2S) -   a compound of Formula (I) wherein R₁ is     4-methylcarbonylamino-phenyl, R₂ is 4-methoxy-phenyl, A-L- is a₁-L₁,     a₁ is pyrrolidin-2-yl, L₁ is methyl, and R_(a) is H; (2S) -   a compound of Formula (I) wherein R₁ is 6-methoxy-pyridin-3-yl, R₂     is 4-amino-phenyl, A-L- is a₁-L₁, a₁ is pyrrolidin-2-yl, L₁ is     methyl, and R_(a) is H; (2S) -   a compound of Formula (I) wherein R₁ is 3-amino-phenyl, R₂ is     4-methoxy-phenyl, A-L- is a₁-L₁, a₁ is pyrrolidin-2-yl, L₁ is     methyl, and R_(a) is H; (2S) -   a compound of Formula (I) wherein R₁ is pyridin-3-yl, R₂ is     4-amino-phenyl, A-L- is a₁-L₁, a₁ is pyrrolidin-2-yl, L₁ is methyl,     and R_(a) is H; (2S) -   a compound of Formula (I) wherein R₁ is benzothiazol-2-yl, R₂ is     4-methoxy-phenyl, A-L- is a₁-L₁, a₁ is pyrrolidin-2-yl, L₁ is     methyl, and R_(a) is H; (2S) -   a compound of Formula (I) wherein R₁ is thiazol-2-yl, R₂ is     4-methoxy-phenyl, A-L- is a₁-L₁, a₁ is pyrrolidin-2-yl, L₁ is     methyl, and R_(a) is H; (2S) -   a compound of Formula (I) wherein R₁ is benzothiophen-2-yl, R₂ is     4-methoxy-phenyl, A-L- is a₁-L₁, a₁ is pyrrolidin-2-yl, L₁ is     methyl, and R_(a) is H; (2S) -   a compound of Formula (I) wherein R₁ is 3-trifluoromethyl-phenyl, R₂     is 4-methoxy-phenyl, A-L- is a₁-L₁, a₁ is pyrrolidin-2-yl, L₁ is     methyl, and R_(a) is H; (2S) -   a compound of Formula (I) wherein R₁ is 3-trifluoromethoxy-phenyl,     R₂ is 4-methoxy-phenyl, A-L- is a₁-L₁, a₁ is pyrrolidin-2-yl, L₁ is     methyl, and R_(a) is H; (2S) -   a compound of Formula (I) wherein R₁ is 2-methylthio-pyrimidin-5-yl,     R₂ is 4-methoxy-phenyl, A-L- is a₁-L₁, a₁ is pyrrolidin-2-yl, L₁ is     methyl, and R_(a) is H; (2S) -   a compound of Formula (I) wherein R₁ is 2-methoxy-pyrimidin-5-yl, R₂     is 4-methoxy-phenyl, A-L- is a₁-L₁, a₁ is pyrrolidin-2-yl, L₁ is     methyl, and R_(a) is H; (2S) -   a compound of Formula (I) wherein R₁ is 5-fluoro-pyridin-3-yl, R₂ is     4-methoxy-phenyl, A-L- is a₁-L₁, a₁ is pyrrolidin-2-yl, L₁ is     methyl, and R_(a) is H; (2S) -   a compound of Formula (I) wherein R₁ is 3,5-difluoro-phenyl, R₂ is     4-methoxy-phenyl, A-L- is a₁-L₁, a₁ is pyrrolidin-2-yl, L₁ is     methyl, and R_(a) is H; (2S) -   a compound of Formula (I) wherein R₁ is 3,4-difluoro-phenyl, R₂ is     4-methoxy-phenyl, A-L- is a₁-L₁, a₁ is pyrrolidin-2-yl, L₁ is     methyl, and R_(a) is H; (2S) -   a compound of Formula (I) wherein R₁ is     3,5-difluoro-4-hydroxymethyl-phenyl, R₂ is 4-methoxy-phenyl, A-L- is     a₁-L₁, a₁ is pyrrolidin-2-yl, L₁ is methyl, and R_(a) is H; (2S) -   a compound of Formula (I) wherein R₁ is     2,4-dimethoxy-pyrimidin-5-yl, R₂ is 4-methoxy-phenyl, A-L- is a₁-L₁,     a₁ is pyrrolidin-2-yl, L₁ is methyl, and R_(a) is H; (2S) -   a compound of Formula (I) wherein R₁ is 6-methoxy-pyridin-3-yl, R₂     is 4-hydroxy-phenyl, A-L- is a₁-L₁, a₁ is pyrrolidin-2-yl, L₁ is     methyl, and R_(a) is H; (2S) -   a compound of Formula (I) wherein R₁ is 2-ethoxy-pyrimidin-5-yl, R₂     is 4-methoxy-phenyl, A-L- is a₁-L₁, a₁ is pyrrolidin-2-yl, L₁ is     methyl, and R_(a) is H; (2S) -   a compound of Formula (I) wherein R₁ is pyrazol-5-yl, R₂ is     4-methoxy-phenyl, A-L- is a₁-L₁, a₁ is pyrrolidin-2-yl, L₁ is     methyl, and R_(a) is H; (2S) -   a compound of Formula (I) wherein R₁ is 3,5-dimethyl-isoxazol-4-yl,     R₂ is 4-methoxy-phenyl, A-L- is a₁-L₁, a₁ is pyrrolidin-2-yl, L₁ is     methyl, and R_(a) is H; (2S) -   a compound of Formula (I) wherein R₁ is 2,3-dihydrobenzofuran5-yl,     R₂ is 4-methoxy-phenyl, A-L- is a₁-L₁, a₁ is pyrrolidin-2-yl, L₁ is     methyl, and R_(a) is H; (2S) -   a compound of Formula (I) wherein R₁ is 3-fluoro-4-methoxy-phenyl,     R₂ is 4-methoxy-phenyl, A-L- is a₁-L₁, a₁ is pyrrolidin-2-yl, L₁ is     methyl, and R_(a) is H; (2S) -   a compound of Formula (I) wherein R₁ is pyrazol-4-yl, R₂ is     4-methoxy-phenyl, A-L- is a₁-L₁, a₁ is pyrrolidin-2-yl, L₁ is     methyl, and R_(a) is H; (2S) -   a compound of Formula (I) wherein R₁ is 2-methylthio-pyrimidin-4-yl,     R₂ is 4-methoxy-phenyl, A-L- is a₁-L₁, a₁ is pyrrolidin-2-yl, L₁ is     methyl, and R_(a) is H; (2S) -   a compound of Formula (I) wherein R₁ is 1-methyl-pyrazol-4-yl, R₂ is     4-methoxy-phenyl, A-L- is a₁-L₁, a₁ is pyrrolidin-2-yl, L₁ is     methyl, and R_(a) is H; (2S) -   a compound of Formula (I) wherein R₁ is 5-methoxy-pyridin-3-yl, R₂     is 4-methoxy-phenyl, A-L- is a₁-L₁, a₁ is pyrrolidin-2-yl, L₁ is     methyl, and R_(a) is H; (2S) -   a compound of Formula (I) wherein R₁ is 5-cyano-pyridin-3-yl, R₂ is     4-methoxy-phenyl, A-L- is a₁-L₁, a₁ is pyrrolidin-2-yl, L₁ is     methyl, and R_(a) is H; (2S) -   a compound of Formula (I) wherein R₁ is 3-fluoro-5-methoxy-phenyl,     R₂ is 4-methoxy-phenyl, A-L- is a₁-L₁, a₁ is pyrrolidin-2-yl, L₁ is     methyl, and R_(a) is H; (2S) -   a compound of Formula (I) wherein R₁ is 3-fluoro-5-methyl-phenyl, R₂     is 4-methoxy-phenyl, A-L- is a₁-L₁, a₁ is pyrrolidin-2-yl, L₁ is     methyl, and R_(a) is H; (2S) -   a compound of Formula (I) wherein R₁ is 6-amino-pyridin-3-yl, R₂ is     4-methoxy-phenyl, A-L- is a₁-L₁, a₁ is pyrrolidin-2-yl, L₁ is     methyl, and R_(a) is H; (2S) -   a compound of Formula (I) wherein R₁ is     5-fluoro-6-methoxy-pyridin-3-yl, R₂ is 4-methoxy-phenyl, A-L- is     a₁-L₁, a₁ is pyrrolidin-2-yl, L₁ is methyl, and R_(a) is H; (2S) -   a compound of Formula (I) wherein R₁ is 6-hydroxy-pyridin-3-yl, R₂     is 4-methoxy-phenyl, A-L- is a₁-L₁, a₁ is pyrrolidin-2-yl, L₁ is     methyl, and R_(a) is H; (2S) -   a compound of Formula (I) wherein R₁ is 6-hydroxy-pyridin-3-yl, R₂     is 4-hydroxy-phenyl, A-L- is a₁-L₁, a₁ is pyrrolidin-2-yl, L₁ is     methyl, and R_(a) is H; (2S) -   a compound of Formula (I) wherein R₁ is quinoxalin-6-yl, R₂ is     4-methoxy-phenyl, A-L- is a₁-L₁, a₁ is pyrrolidin-2-yl, L₁ is     methyl, and R_(a) is H; (2S) -   a compound of Formula (I) wherein R₁ is     1H-pyrrolo[2,3-b]pyridin-5-yl, R₂ is 4-methoxy-phenyl, A-L- is     a₁-L₁, a₁ is pyrrolidin-2-yl, L₁ is methyl, and R_(a) is H; (2S) -   a compound of Formula (I) wherein R₁ is benzo[1,2,5]oxadiazol-5-yl,     R₂ is 4-methoxy-phenyl, A-L- is a₁-L₁, a₁ is pyrrolidin-2-yl, L₁ is     methyl, and R_(a) is H; (2S) -   a compound of Formula (I) wherein R₁ is pyrimidin-5-yl, R₂ is     4-methoxy-phenyl, A-L- is a₁-L₁, a₁ is 4,4-difluoro-pyrrolidin-2-yl,     L₁ is methyl, and R_(a) is H; (2S) -   a compound of Formula (I) wherein R₁ is pyrimidin-5-yl, R₂ is     4-methoxy-phenyl, A-L- is a₁-L₁, a₁ is 4-fluoro-pyrrolidin-2-yl, L₁     is methyl, and R_(a) is H; (2S,4R) -   a compound of Formula (I) wherein R₁ is 2-amino-pyrimidin-5-yl, R₂     is 4-methoxy-phenyl, A-L- is a₁-L₁, a₁ is pyrrolidin-2-yl, L₁ is     methyl, and R_(a) is H; (2S) -   a compound of Formula (I) wherein R₁ is     2-dimethylamino-pyrimidin-5-yl, R₂ is 4-methoxy-phenyl, A-L- is     a₁-L₁, a₁ is pyrrolidin-2-yl, L₁ is methyl, and R_(a) is H; (2S) -   a compound of Formula (I) wherein R₁ is     2-(morpholin-4-yl)-pyrimidin-5-yl, R₂ is 4-methoxy-phenyl, A-L- is     a₁-L₁, a₁ is pyrrolidin-2-yl, L₁ is methyl, and R_(a) is H; (2S) -   a compound of Formula (I) wherein R₁ is     2-(4-methyl-pyrazin-1-yl)-pyrimidin-5-yl, R₂ is 4-methoxy-phenyl,     A-L- is a₁-L₁, a₁ is pyrrolidin-2-yl, L₁ is methyl, and R_(a) is H;     (2S) -   a compound of Formula (I) wherein R₁ is pyrimidin-5-yl, R₂ is     benzothiazol-6-yl, A-L- is a₁-L₁, a₁ is pyrrolidin-2-yl, L₁ is     methyl, and R_(a) is H; (2S) -   a compound of Formula (I) wherein R₁ is 5-cyano-pyridin-3-yl, R₂ is     benzothiazol-6-yl, A-L- is a₁-L₁, a₁ is pyrrolidin-2-yl, L₁ is     methyl, and R_(a) is H; (2S) -   a compound of Formula (I) wherein R₁ is pyrimidin-5-yl, R₂ is     2-methyl-benzoxazol-6-yl, A-L- is a₁-L₁, a₁ is pyrrolidin-2-yl, L₁     is methyl, and R_(a) is H; (2S) -   a compound of Formula (I) wherein R₁ is 5-cyano-pyridin-3-yl, R₂ is     2-methyl-benzoxazol-6-yl, A-L- is a₁-L₁, a₁ is pyrrolidin-2-yl, L₁     is methyl, and R_(a) is H; (2S) -   a compound of Formula (I) wherein R₁ is pyrimidin-5-yl, R₂ is     4-methoxy-phenyl, A-L- is a₁-L₁, a₁ is 4-fluoro-pyrrolidin-2-yl, L₁     is methyl, and R_(a) is H; (2S,4S) -   a compound of Formula (I) wherein R₁ is 5-cyano-pyridin-3-yl, R₂ is     2-methyl-benzothiazol-6-yl, A-L- is a₁-L₁, a₁ is pyrrolidin-2-yl, L₁     is methyl, and R_(a) is H; (2S) -   a compound of Formula (I) wherein R₁ is pyrimidin-5-yl, R₂ is     2-methyl-benzothiazol-6-yl, A-L- is a₁-L₁, a₁ is pyrrolidin-2-yl, L₁     is methyl, and R_(a) is H; (2S) -   a compound of Formula (I) wherein R₁ is 3,5-dimethyl-phenyl, R₂ is     4-methoxy-phenyl, A-L- is a₁-L₁, a₁ is pyrrolidin-2-yl, L₁ is     methyl, and R_(a) is H; (2S) -   a compound of Formula (I) wherein R₁ is benzo[1,3]dioxol-5-yl, R₂ is     4-methoxy-phenyl, A-L- is a₁-L₁, a₁ is pyrrolidin-2-yl, L₁ is     methyl, and R_(a) is H; (2S) -   a compound of Formula (I) wherein R₁ is 3,5-dichloro-phenyl, R₂ is     4-methoxy-phenyl, A-L- is a₁-L₁, a₁ is pyrrolidin-2-yl, L₁ is     methyl, and R_(a) is H; (2S) -   a compound of Formula (I) wherein R₁ is 6-cyano-pyridin-3-yl, R₂ is     4-methoxy-phenyl, A-L- is a₁-L₁, a₁ is pyrrolidin-2-yl, L₁ is     methyl, and R_(a) is H; (2S) -   a compound of Formula (I) wherein R₁ is 5-cyano-pyridin-3-yl, R₂ is     3,5-difluoro-4-methoxy-phenyl, A-L- is a₁-L₁, a₁ is pyrrolidin-2-yl,     L₁ is methyl, and R_(a) is H; (2S) -   a compound of Formula (I) wherein R₁ is pyrimidin-5-yl, R₂ is     3,5-difluoro-4-methoxy-phenyl, A-L- is a₁-L₁, a₁ is pyrrolidin-2-yl,     L₁ is methyl, and R_(a) is H; (2S) -   a compound of Formula (I) wherein R₁ is 5-cyano-pyridin-3-yl, R₂ is     3-methoxy-phenyl, A-L- is a₁-L₁, a₁ is pyrrolidin-2-yl, L₁ is     methyl, and R_(a) is H; (2S) -   a compound of Formula (I) wherein R₁ is pyrimidin-5-yl, R₂ is     3-methoxy-phenyl, A-L- is a₁-L₁, a₁ is pyrrolidin-2-yl, L₁ is     methyl, and R_(a) is H; (2S) -   a compound of Formula (I) wherein R₁ is pyridin-3-yl, R₂ is     3-methoxy-phenyl, A-L- is a₁-L₁, a₁ is pyrrolidin-2-yl, L₁ is     methyl, and R_(a) is H; (2S) -   a compound of Formula (I) wherein R₁ is 5-cyano-pyridin-3-yl, R₂ is     2,3-difluoro-4-methoxy-phenyl, A-L- is a₁-L₁, a₁ is pyrrolidin-2-yl,     L₁ is methyl, and R_(a) is H; (2S) -   a compound of Formula (I) wherein R₁ is 5-fluoro-pyridin-3-yl, R₂ is     2,3-difluoro-4-methoxy-phenyl, A-L- is a₁-L₁, a₁ is pyrrolidin-2-yl,     L₁ is methyl, and R_(a) is H; (2S) -   a compound of Formula (I) wherein R₁ is pyrimidin-5-yl, R₂ is     2,3-difluoro-4-methoxy-phenyl, A-L- is a₁-L₁, a₁ is pyrrolidin-2-yl,     L₁ is methyl, and R_(a) is H; (2S) -   a compound of Formula (I) wherein R₁ is 5-cyano-pyridin-3-yl, R₂ is     4-ethoxy-phenyl, A-L- is a₁-L₁, a₁ is pyrrolidin-2-yl, L₁ is methyl,     and R_(a) is H; (2S) -   a compound of Formula (I) wherein R₁ is pyrimidin-5-yl, R₂ is     4-ethoxy-phenyl, A-L- is a₁-L₁, a₁ is pyrrolidin-2-yl, L₁ is methyl,     and R_(a) is H; (2S) -   a compound of Formula (I) wherein R₁ is 5-fluoro-pyridin-3-yl, R₂ is     4-ethoxy-phenyl, A-L- is a₁-L₁, a₁ is pyrrolidin-2-yl, L₁ is methyl,     and R_(a) is H; (2S) -   a compound of Formula (I) wherein R₁ is 5-methylthio-pyridin-3-yl,     R₂ is 4-methoxy-phenyl, A-L- is a₁-L₁, a₁ is pyrrolidin-2-yl, L₁ is     methyl, and R_(a) is H; (2S) -   a compound of Formula (I) wherein R₁ is     5-methanesulfonyl-pyridin-3-yl, R₂ is 4-methoxy-phenyl, A-L- is     a₁-L₁, a₁ is pyrrolidin-2-yl, L₁ is methyl, and R_(a) is H; (2S) -   a compound of Formula (I) wherein R₁ is pyrimidin-5-yl, R₂ is     4-methoxy-phenyl, A-L- is a₁-L₁, a₁ is piperidin-3-yl, L₁ is absent,     and R_(a) is H; (racemic) -   a compound of Formula (I) wherein R₁ is 5-cyano-pyridin-3-yl, R₂ is     4-difluoromethoxy-phenyl, A-L- is a₁-L₁, a₁ is pyrrolidin-2-yl, L₁     is methyl, and R_(a) is H; (2S) -   a compound of Formula (I) wherein R₁ is pyrimidin-5-yl, R₂ is     4-difluoromethoxy-phenyl, A-L- is a₁-L₁, a₁ is pyrrolidin-2-yl, L₁     is methyl, and R_(a) is H; (2S) -   a compound of Formula (I) wherein R₁ is 5-fluoro-pyridin-3-yl, R₂ is     4-difluoromethoxy-phenyl, A-L- is a₁-L₁, a₁ is pyrrolidin-2-yl, L₁     is methyl, and R_(a) is H; (2S) -   a compound of Formula (I) wherein R₁ is 5-cyano-pyridin-3-yl, R₂ is     4-n-propyloxy-phenyl, A-L- is a₁-L₁, a₁ is pyrrolidin-2-yl, L₁ is     methyl, and R_(a) is H; (2S) -   a compound of Formula (I) wherein R₁ is pyrimidin-5-yl, R₂ is     4-n-propyloxy-phenyl, A-L- is a₁-L₁, a₁ is pyrrolidin-2-yl, L₁ is     methyl, and R_(a) is H; (2S) -   a compound of Formula (I) wherein R₁ is 5-fluoro-pyridin-3-yl, R₂ is     4-n-propyloxy-phenyl, A-L- is a₁-L₁, a₁ is pyrrolidin-2-yl, L₁ is     methyl, and R_(a) is H; (2S) -   a compound of Formula (I) wherein R₁ is indol-4-yl, R₂ is     4-methoxy-phenyl, A-L- is a₁-L₁, a₁ is pyrrolidin-2-yl, L₁ is     methyl, and R_(a) is H; (2S) -   a compound of Formula (I) wherein R₁ is indol-6-yl, R₂ is     4-methoxy-phenyl, A-L- is a₁-L₁, a₁ is pyrrolidin-2-yl, L₁ is     methyl, and R_(a) is H; (2S) -   a compound of Formula (I) wherein R₁ is indol-7-yl, R₂ is     4-methoxy-phenyl, A-L- is a₁-L₁, a₁ is pyrrolidin-2-yl, L₁ is     methyl, and R_(a) is H; (2S) -   a compound of Formula (I) wherein R₁ is pyrazin-2-yl, R₂ is     4-methoxy-phenyl, A-L- is a₁-L₁, a₁ is pyrrolidin-2-yl, L₁ is     methyl, and R_(a) is H; (2S) -   a compound of Formula (I) wherein R₁ is 2-cyano-pyrimidin-5-yl, R₂     is 4-methoxy-phenyl, A-L- is a₁-L₁, a₁ is pyrrolidin-2-yl, L₁ is     methyl, and R_(a) is H; (2S) -   a compound of Formula (I) wherein R₁ is 5-cyano-pyridin-3-yl, R₂ is     4-(2,2,2-trifluoro-ethoxy)-phenyl, A-L- is a₁-L₁, a₁ is     pyrrolidin-2-yl, L₁ is methyl, and R_(a) is H; (2S) -   a compound of Formula (I) wherein R₁ is pyrimidin-5-yl, R₂ is     4-(2,2,2-trifluoro-ethoxy)-phenyl, A-L- is a₁-L₁, a₁ is     pyrrolidin-2-yl, L₁ is methyl, and R_(a) is H; (2S) -   a compound of Formula (I) wherein R₁ is 5-fluoro-pyridin-3-yl, R₂ is     4-(2,2,2-trifluoro-ethoxy)-phenyl, A-L- is a₁-L₁, a₁ is     pyrrolidin-2-yl, L₁ is methyl, and R_(a) is H; (2S) -   a compound of Formula (I) wherein R₁ is 5-cyano-pyridin-3-yl, R₂ is     4-n-butoxy-phenyl, A-L- is a₁-L₁, a₁ is pyrrolidin-2-yl, L₁ is     methyl, and R_(a) is H; (2S) -   a compound of Formula (I) wherein R₁ is pyrimidin-5-yl, R₂ is     4-n-butoxy-phenyl, A-L- is a₁-L₁, a₁ is pyrrolidin-2-yl, L₁ is     methyl, and R_(a) is H; (2S) -   a compound of Formula (I) wherein R₁ is 5-fluoro-pyridin-3-yl, R₂ is     4-n-butoxy-phenyl, A-L- is a₁-L₁, a₁ is pyrrolidin-2-yl, L₁ is     methyl, and R_(a) is H; (2S) -   a compound of Formula (I) wherein R₁ is 5-fluoro-pyridin-3-yl, R₂ is     4-chloro-phenyl, A-L- is a₁-L₁, a₁ is pyrrolidin-2-yl, L₁ is methyl,     and R_(a) is H; (2S) -   a compound of Formula (I) wherein R₁ is 5-cyano-pyridin-3-yl, R₂ is     4-chloro-phenyl, A-L- is a₁-L₁, a₁ is pyrrolidin-2-yl, L₁ is methyl,     and R_(a) is H; (2S) -   a compound of Formula (I) wherein R₁ is pyrimidin-5-yl, R₂ is     4-chloro-phenyl, A-L- is a₁-L₁, a₁ is pyrrolidin-2-yl, L₁ is methyl,     and R_(a) is H; (2S) -   a compound of Formula (I) wherein R₁ is 5-fluoro-pyridin-3-yl, R₂ is     3-fluoro-4-methoxy-phenyl, A-L- is a₁-L₁, a₁ is pyrrolidin-2-yl, L₁     is methyl, and R_(a) is H; (2S) -   a compound of Formula (I) wherein R₁ is 5-cyano-pyridin-3-yl, R₂ is     3-fluoro-4-methoxy-phenyl, A-L- is a₁-L₁, a₁ is pyrrolidin-2-yl, L₁     is methyl, and R_(a) is H; (2S) -   a compound of Formula (I) wherein R₁ is pyrimidin-5-yl, R₂ is     3-fluoro-4-methoxy-phenyl, A-L- is a₁-L₁, a₁ is pyrrolidin-2-yl, L₁     is methyl, and R_(a) is H; (2S) -   a compound of Formula (I) wherein R₁ is 5-cyano-pyridin-3-yl, R₂ is     4-methoxy-phenyl, A-L- is a₁-L₁, a₁ is 4-fluoro-pyrrolidin-2-yl, L₁     is methyl, and R_(a) is H; (2S,4R) -   a compound of Formula (I) wherein R₁ is pyridin-3-yl, R₂ is     3-cyano-phenyl, A-L- is a₁-L₁, a₁ is pyrrolidin-2-yl, L₁ is methyl,     and R_(a) is H; (2S) -   a compound of Formula (I) wherein R₁ is pyridin-3-yl, R₂ is     4-cyano-phenyl, A-L- is a₁-L₁, a₁ is pyrrolidin-2-yl, L₁ is methyl,     and R_(a) is H; (2S) -   a compound of Formula (I) wherein R₁ is pyridin-3-yl, R₂ is     3-fluoro-4-cyano-phenyl, A-L- is a₁-L₁, a₁ is pyrrolidin-2-yl, L₁ is     methyl, and R_(a) is H; (2S) -   a compound of Formula (I) wherein R₁ is pyridin-3-yl, R₂ is     4-cyclopropylcarbonylamino-phenyl, A-L- is a₁-L₁, a₁ is     pyrrolidin-2-yl, L₁ is methyl, and R_(a) is H; (2S) -   a compound of Formula (I) wherein R₁ is 5-cyano-pyridin-3-yl, R₂ is     4-isopropyloxy-phenyl, A-L- is a₁-L₁, a₁ is pyrrolidin-2-yl, L₁ is     methyl, and R_(a) is H; (2S) -   a compound of Formula (I) wherein R₁ is pyrimidin-5-yl, R₂ is     4-isopropyloxy-phenyl, A-L- is a₁-L₁, a₁ is pyrrolidin-2-yl, L₁ is     methyl, and R_(a) is H; (2S) -   a compound of Formula (I) wherein R₁ is pyridin-3-yl, R₂ is     4-isopropyloxy-phenyl, A-L- is a₁-L₁, a₁ is pyrrolidin-2-yl, L₁ is     methyl, and R_(a) is H; (2S) -   a compound of Formula (I) wherein R₁ is 3-cyano-5-fluoro-phenyl, R₂     is 4-methoxy-phenyl, A-L- is a₁-L₁, a₁ is pyrrolidin-2-yl, L₁ is     methyl, and R_(a) is H; (2S) -   a compound of Formula (I) wherein R₁ is 5-cyano-pyridin-3-yl, R₂ is     4-hydroxymethyl-phenyl, A-L- is a₁-L₁, a₁ is pyrrolidin-2-yl, L₁ is     methyl, and R_(a) is H; (2S) -   a compound of Formula (I) wherein R₁ is pyrimidin-5-yl, R₂ is     4-hydroxymethyl-phenyl, A-L- is a₁-L₁, a₁ is pyrrolidin-2-yl, L₁ is     methyl, and R_(a) is H; (2S) -   a compound of Formula (I) wherein R₁ is pyridin-3-yl, R₂ is     4-hydroxymethyl-phenyl, A-L- is a₁-L₁, a₁ is pyrrolidin-2-yl, L₁ is     methyl, and R_(a) is H; (2S) -   a compound of Formula (I) wherein R₁ is 5-cyano-pyridin-3-yl, R₂ is     4-fluoro-phenyl, A-L- is a₁-L₁, a₁ is pyrrolidin-2-yl, L₁ is methyl,     and R_(a) is H; (2S) -   a compound of Formula (I) wherein R₁ is 5-cyano-pyridin-3-yl, R₂ is     4-methyl-phenyl, A-L- is a₁-L₁, a₁ is pyrrolidin-2-yl, L₁ is methyl,     and R_(a) is H; (2S) -   a compound of Formula (I) wherein R₁ is pyrimidin-5-yl, R₂ is     4-methyl-phenyl, A-L- is a₁-L₁, a₁ is pyrrolidin-2-yl, L₁ is methyl,     and R_(a) is H; (2S) -   a compound of Formula (I) wherein R₁ is pyridin-3-yl, R₂ is     4-methyl-phenyl, A-L- is a₁-L₁, a₁ is pyrrolidin-2-yl, L₁ is methyl,     and R_(a) is H; (2S) -   a compound of Formula (I) wherein R₁ is 5-cyano-pyridin-3-yl, R₂ is     4-methylthio-phenyl, A-L- is a₁-L₁, a₁ is pyrrolidin-2-yl, L₁ is     methyl, and R_(a) is H; (2S) -   a compound of Formula (I) wherein R₁ is pyrimidin-5-yl, R₂ is     4-methylthio-phenyl, A-L- is a₁-L₁, a₁ is pyrrolidin-2-yl, L₁ is     methyl, and R_(a) is H; (2S) -   a compound of Formula (I) wherein R₁ is pyridin-3-yl, R₂ is     4-methylthio-phenyl, A-L- is a₁-L₁, a₁ is pyrrolidin-2-yl, L₁ is     methyl, and R_(a) is H; (2S) -   a compound of Formula (I) wherein R₁ is 5-cyano-pyridin-3-yl, R₂ is     4-methoxymethyl-phenyl, A-L- is a₁-L₁, a₁ is pyrrolidin-2-yl, L₁ is     methyl, and R_(a) is H; (2S) -   a compound of Formula (I) wherein R₁ is pyrimidin-5-yl, R₂ is     4-methoxymethyl-phenyl, A-L- is a₁-L₁, a₁ is pyrrolidin-2-yl, L₁ is     methyl, and R_(a) is H; (2S) -   a compound of Formula (I) wherein R₁ is pyridin-3-yl, R₂ is     4-methoxymethyl-phenyl, A-L- is a₁-L₁, a₁ is pyrrolidin-2-yl, L₁ is     methyl, and R_(a) is H; (2S) -   a compound of Formula (I) wherein R₁ is pyrimidin-5-yl, R₂ is     4-hydroxy-phenyl, A-L- is a₁-L₁, a₁ is pyrrolidin-2-yl, L₁ is     methyl, and R_(a) is H; (2S) -   a compound of Formula (I) wherein R₁ is pyridin-3-yl, R₂ is     3-diethylaminocarbonyl-phenyl, A-L- is a₁-L₁, a₁ is pyrrolidin-2-yl,     L₁ is methyl, and R_(a) is H; (2S) -   a compound of Formula (I) wherein R₁ is pyridin-3-yl, R₂ is     4-pyrrolidin-1-ylcarbonyl-phenyl, A-L- is a₁-L₁, a₁ is     pyrrolidin-2-yl, L₁ is methyl, and R_(a) is H; (2S) -   a compound of Formula (I) wherein R₁ is pyridin-3-yl, R₂ is     4-carboxy-phenyl, A-L- is a₁-L₁, a₁ is pyrrolidin-2-yl, L₁ is     methyl, and R_(a) is H; (2S) -   a compound of Formula (I) wherein R₁ is pyridin-3-yl, R₂ is     4-piperidin-1-ylcarbonyl-phenyl, A-L- is a₁-L₁, a₁ is     pyrrolidin-2-yl, L₁ is methyl, and R_(a) is H; (2S) -   a compound of Formula (I) wherein R₁ is pyridin-3-yl, R₂ is     4-(morpholin-4-ylcarbonyl)-phenyl, A-L- is a₁-L₁, a₁ is     pyrrolidin-2-yl, L₁ is methyl, and R_(a) is H; (2S) -   a compound of Formula (I) wherein R₁ is pyridin-3-yl, R₂ is     4-(4-methyl-piperazin-1-ylcarbonyl)-phenyl, A-L- is a₁-L₁, a₁ is     pyrrolidin-2-yl, L₁ is methyl, and R_(a) is H; (2S) -   a compound of Formula (I) wherein R₁ is pyridin-3-yl, R₂ is     3-carboxy-phenyl, A-L- is a₁-L₁, a₁ is pyrrolidin-2-yl, L₁ is     methyl, and R_(a) is H; (2S) -   a compound of Formula (I) wherein R₁ is 5-fluoro-pyridin-3-yl, R₂ is     3-carboxy-phenyl, A-L- is a₁-L₁, a₁ is pyrrolidin-2-yl, L₁ is     methyl, and R_(a) is H; (2S) -   a compound of Formula (I) wherein R₁ is 5-fluoro-pyridin-3-yl, R₂ is     4-carboxy-phenyl, A-L- is a₁-L₁, a₁ is pyrrolidin-2-yl, L₁ is     methyl, and R_(a) is H; (2S) -   a compound of Formula (I) wherein R₁ is pyridin-3-yl, R₂ is     3-(pyrrolidin-1-ylcarbonyl)-phenyl, A-L- is a₁-L₁, a₁ is     pyrrolidin-2-yl, L₁ is methyl, and R_(a) is H; (2S) -   a compound of Formula (I) wherein R₁ is pyridin-3-yl, R₂ is     3-(piperidin-1-ylcarbonyl)-phenyl, A-L- is a₁-L₁, a₁ is     pyrrolidin-2-yl, L₁ is methyl, and R_(a) is H; (2S) -   a compound of Formula (I) wherein R₁ is pyridin-3-yl, R₂ is     3-(morpholin-4-ylcarbonyl)-phenyl, A-L- is a₁-L₁, a₁ is     pyrrolidin-2-yl, L₁ is methyl, and R_(a) is H; (2S) -   a compound of Formula (I) wherein R₁ is pyridin-3-yl, R₂ is     3-(4-methyl-piperazin-1-ylcarbonyl)-phenyl, A-L- is a₁-L₁, a₁ is     pyrrolidin-2-yl, L₁ is methyl, and R_(a) is H; (2S) -   a compound of Formula (I) wherein R₁ is 5-fluoro-pyridin-3-yl, R₂ is     3-diethylaminocarbonyl-phenyl, A-L- is a₁-L₁, a₁ is pyrrolidin-2-yl,     L₁ is methyl, and R_(a) is H; (2S) -   a compound of Formula (I) wherein R₁ is 5-fluoro-pyridin-3-yl, R₂ is     3-(pyrrolidin-1-ylcarbonyl)-phenyl, A-L- is a₁-L₁, a₁ is     pyrrolidin-2-yl, L₁ is methyl, and R_(a) is H; (2S) -   a compound of Formula (I) wherein R₁ is 5-fluoro-pyridin-3-yl, R₂ is     3-(piperidin-1-ylcarbonyl)-phenyl, A-L- is a₁-L₁, a₁ is     pyrrolidin-2-yl, L₁ is methyl, and R_(a) is H; (2S) -   a compound of Formula (I) wherein R₁ is 5-fluoro-pyridin-3-yl, R₂ is     3-(morpholin-4-ylcarbonyl)-phenyl, A-L- is a₁-L₁, a₁ is     pyrrolidin-2-yl, L₁ is methyl, and R_(a) is H; (2S) -   a compound of Formula (I) wherein R₁ is 5-fluoro-pyridin-3-yl, R₂ is     3-(4-methyl-piperazin-1-ylcarbonyl)-phenyl, A-L- is a₁-L₁, a₁ is     pyrrolidin-2-yl, L₁ is methyl, and R_(a) is H; (2S) -   a compound of Formula (I) wherein R₁ is pyridin-3-yl, R₂ is     4-diethylaminocarbonyl-phenyl, A-L- is a₁-L₁, a₁ is pyrrolidin-2-yl,     L₁ is methyl, and R_(a) is H; (2S) -   a compound of Formula (I) wherein R₁ is 5-fluoro-pyridin-3-yl, R₂ is     4-(pyrrolidin-1-ylcarbonyl)-phenyl, A-L- is a₁-L₁, a₁ is     pyrrolidin-2-yl, L₁ is methyl, and R_(a) is H; (2S) -   a compound of Formula (I) wherein R₁ is pyridin-3-yl, R₂ is     4-benzyloxycarbonylamino-phenyl, A-L- is a₁-L₁, a₁ is     pyrrolidin-2-yl, L₁ is methyl, and R_(a) is H; (2S) -   a compound of Formula (I) wherein R₁ is 5-fluoro-pyridin-3-yl, R₂ is     4-methyl-phenyl, A-L- is a₁-L₁, a₁ is pyrrolidin-2-yl, L₁ is methyl,     and R_(a) is H; (2S) -   a compound of Formula (I) wherein R₁ is 5-cyano-pyridin-3-yl, R₂ is     4-ethyl-phenyl, A-L- is a₁-L₁, a₁ is pyrrolidin-2-yl, L₁ is methyl,     and R_(a) is H; (2S) -   a compound of Formula (I) wherein R₁ is 5-chloro-pyridin-3-yl, R₂ is     4-ethyl-phenyl, A-L- is a₁-L₁, a₁ is pyrrolidin-2-yl, L₁ is methyl,     and R_(a) is H; (2S) -   a compound of Formula (I) wherein R₁ is pyrimidin-5-yl, R₂ is     4-methoxy-phenyl, A-L- is a₁-L₁, a₁ is pyrrolidin-2-yl, L₁ is     methyl, R_(a) is methylcarbonyl; (2S) -   a compound of Formula (I) wherein R₁ is 5-fluoro-pyridin-3-yl, R₂ is     4-ethyl-phenyl, A-L- is a₁-L₁, a₁ is pyrrolidin-2-yl, L₁ is methyl,     and R_(a) is H; (2S) -   a compound of Formula (I) wherein R₁ is 5-cyano-pyridin-3-yl, R₂ is     3-fluoro-4-methyl-phenyl, A-L- is a₁-L₁, a₁ is pyrrolidin-2-yl, L₁     is methyl, and R_(a) is H; (2S) -   a compound of Formula (I) wherein R₁ is pyridin-3-yl, R₂ is     4-ethyl-phenyl, A-L- is a₁-L₁, a₁ is pyrrolidin-2-yl, L₁ is methyl,     and R_(a) is H; (2S) -   a compound of Formula (I) wherein R₁ is 5-fluoro-pyridin-3-yl, R₂ is     3-fluoro-4-methyl-phenyl, A-L- is a₁-L₁, a₁ is pyrrolidin-2-yl, L₁     is methyl, and R_(a) is H; (2S) -   a compound of Formula (I) wherein R₁ is 5-chloro-pyridin-3-yl, R₂ is     3-fluoro-4-methyl-phenyl, A-L- is a₁-L₁, a₁ is pyrrolidin-2-yl, L₁     is methyl, and R_(a) is H; (2S) -   a compound of Formula (I) wherein R₁ is pyridin-3-yl, R₂ is     3-fluoro-4-methyl-phenyl, A-L- is a₁-L₁, a₁ is pyrrolidin-2-yl, L₁     is methyl, and R_(a) is H; (2S) -   a compound of Formula (I) wherein R₁ is pyridin-3-yl, R₂ is     3-benzyloxycarbonylamino-phenyl, A-L- is a₁-L₁, a₁ is     pyrrolidin-2-yl, L₁ is methyl, and R_(a) is H; (2S) -   a compound of Formula (I) wherein R₁ is 5-cyano-pyridin-3-yl, R₂ is     2,3-difluoro-4-methyl-phenyl, A-L- is a₁-L₁, a₁ is pyrrolidin-2-yl,     L₁ is methyl, and R_(a) is H; (2S) -   a compound of Formula (I) wherein R₁ is 5-chloro-pyridin-3-yl, R₂ is     2,3-difluoro-4-methyl-phenyl, A-L- is a₁-L₁, a₁ is pyrrolidin-2-yl,     L₁ is methyl, and R_(a) is H; (2S) -   a compound of Formula (I) wherein R₁ is 5-fluoro-pyridin-3-yl, R₂ is     2,3-difluoro-4-methyl-phenyl, A-L- is a₁-L₁, a₁ is pyrrolidin-2-yl,     L₁ is methyl, and R_(a) is H; (2S) -   a compound of Formula (I) wherein R₁ is pyridin-3-yl, R₂ is     2,3-difluoro-4-methyl-phenyl, A-L- is a₁-L₁, a₁ is pyrrolidin-2-yl,     L₁ is methyl, and R_(a) is H; (2S) -   a compound of Formula (I) wherein R₁ is 5-fluoro-pyridin-3-yl, R₂ is     4-methoxy-phenyl, A-L- is a₁-L₁, a₁ is 4-fluoro-pyrrolidin-2-yl, L₁     is methyl, and R_(a) is H; (2S,4R) -   a compound of Formula (I) wherein R₁ is 5-chloro-pyridin-3-yl, R₂ is     4-methoxy-phenyl, A-L- is a₁-L₁, a₁ is 4-fluoro-pyrrolidin-2-yl, L₁     is methyl, and R_(a) is H; (2S,4R) -   a compound of Formula (I) wherein R₁ is 5-cyano-pyridin-3-yl, R₂ is     4-ethyl-phenyl, A-L- is a₁-L₁, a₁ is 4-fluoro-pyrrolidin-2-yl, L₁ is     methyl, and R_(a) is H; (2S,4R) -   a compound of Formula (I) wherein R₁ is pyridin-3-yl, R₂ is     4-methoxy-phenyl, A-L- is a₁-L₁, a₁ is 4-fluoro-pyrrolidin-2-yl, L₁     is methyl, and R_(a) is H; (2S,4R) -   a compound of Formula (I) wherein R₁ is 5-fluoro-pyridin-3-yl, R₂ is     4-benzyloxycarbonylamino-phenyl, A-L- is a₁-L₁, a₁ is     pyrrolidin-2-yl, L₁ is methyl, and R_(a) is H; (2S) -   a compound of Formula (I) wherein R₁ is 5-fluoro-pyridin-3-yl, R₂ is     4-amino-phenyl, A-L- is a₁-L₁, a₁ is pyrrolidin-2-yl, L₁ is methyl,     and R_(a) is H; (2S) -   a compound of Formula (I) wherein R₁ is 5-cyano-pyridin-3-yl, R₂ is     4-methoxy-phenyl, A-L- is a₁-L₁, a₁ is piperidin-3-yl, L₁ is absent,     and R_(a) is H; (3S) -   a compound of Formula (I) wherein R₁ is 5-cyano-pyridin-3-yl, R₂ is     3-methyl-phenyl, A-L- is a₁-L₁, a₁ is pyrrolidin-2-yl, L₁ is methyl,     and R_(a) is H; (2S) -   a compound of Formula (I) wherein R₁ is 5-chloro-pyridin-3-yl, R₂ is     3-methyl-phenyl, A-L- is a₁-L₁, a₁ is pyrrolidin-2-yl, L₁ is methyl,     and R_(a) is H; (2S) -   a compound of Formula (I) wherein R₁ is 5-fluoro-pyridin-3-yl, R₂ is     3-methyl-phenyl, A-L- is a₁-L₁, a₁ is pyrrolidin-2-yl, L₁ is methyl,     and R_(a) is H; (2S) -   a compound of Formula (I) wherein R₁ is pyridin-3-yl, R₂ is     3-methyl-phenyl, A-L- is a₁-L₁, a₁ is pyrrolidin-2-yl, L₁ is methyl,     and R_(a) is H; (2S) -   a compound of Formula (I) wherein R₁ is 5-cyano-pyridin-3-yl, R₂ is     3-methyl-4-methoxy-phenyl, A-L- is a₁-L₁, a₁ is pyrrolidin-2-yl, L₁     is methyl, and R_(a) is H; (2S) -   a compound of Formula (I) wherein R₁ is 5-fluoro-pyridin-3-yl, R₂ is     3-methyl-4-methoxy-phenyl, A-L- is a₁-L₁, a₁ is pyrrolidin-2-yl, L₁     is methyl, and R_(a) is H; (2S) -   a compound of Formula (I) wherein R₁ is 5-cyano-pyridin-3-yl, R₂ is     4-fluoromethyl-phenyl, A-L- is a₁-L₁, a₁ is pyrrolidin-2-yl, L₁ is     methyl, and R_(a) is H; (2S) -   a compound of Formula (I) wherein R₁ is 5-cyano-pyridin-3-yl, R₂ is     4-methoxy-phenyl, A-L- is a₁-L₁, a₁ is piperidin-3-yl, L₁ is absent,     and R_(a) is H; (3S) -   a compound of Formula (I) wherein R₁ is 5-cyano-pyridin-3-yl, R₂ is     4-methoxy-phenyl, A-L- is a₁-L₁, a₁ is piperidin-4-yl, L₁ is absent,     and R_(a) is H; -   a compound of Formula (I) wherein R₁ is pyridin-3-yl, R₂ is     4-(pyridin-3-ylmethyl)-phenyl, A-L- is a₁-L₁, a₁ is pyrrolidin-2-yl,     L₁ is methyl, and R_(a) is H; (2S) -   a compound of Formula (I) wherein R₁ is 5-chloro-pyridin-3-yl, R₂ is     3-methyl-4-methoxy-phenyl, A-L- is a₁-L₁, a₁ is pyrrolidin-2-yl, L₁     is methyl, and R_(a) is H; (2S) -   a compound of Formula (I) wherein R₁ is pyridin-3-yl, R₂ is     3-methyl-4-methoxy-phenyl, A-L- is a₁-L₁, a₁ is pyrrolidin-2-yl, L₁     is methyl, and R_(a) is H; (2S) -   a compound of Formula (I) wherein R₁ is 5-cyano-pyridin-3-yl, R₂ is     4-methoxy-phenyl, A-L- is a₁-L₁, a₁ is pyrrolidin-2-yl, L₁ is     methyl, and R_(a) is H; (2S) -   a compound of Formula (I) wherein R₁ is 5-fluoro-pyridin-3-yl, R₂ is     4-methylcarbonylamino-phenyl, A-L- is a₁-L₁, a₁ is pyrrolidin-2-yl,     L₁ is methyl, and R_(a) is H; (2S) -   a compound of Formula (I) wherein R₁ is 5-fluoro-pyridin-3-yl, R₂ is     4-methanesulfonylamino-phenyl, A-L- is a₁-L₁, a₁ is pyrrolidin-2-yl,     L₁ is methyl, and R_(a) is H; (2S) -   a compound of Formula (I) wherein R₁ is pyridin-3-yl, R₂ is     4-methanesulfonylamino-phenyl, A-L- is a₁-L₁, a₁ is pyrrolidin-2-yl,     L₁ is methyl, and R_(a) is H; (2S) -   a compound of Formula (I) wherein R₁ is 5-cyano-pyridin-3-yl, R₂ is     4-methoxy-phenyl, A-L- is a₁-L₁, a₁ is azetidin-3-yl, L₁ is methyl,     and R_(a) is H; (2S) -   a compound of Formula (I) wherein R₁ is pyridin-3-yl, R₂ is     4-formamido-phenyl, A-L- is a₁-L₁, a₁ is pyrrolidin-2-yl, L₁ is     methyl, and R_(a) is H; (2S) -   a compound of Formula (I) wherein R₁ is pyridin-3-yl, R₂ is     4-fluoromethyl-phenyl, A-L- is a₁-L₁, a₁ is pyrrolidin-2-yl, L₁ is     methyl, and R_(a) is H; (2S) -   a compound of Formula (I) wherein R₁ is 5-cyano-pyridin-3-yl, R₂ is     3-methyl-4-fluoro-phenyl, A-L- is a₁-L₁, a₁ is pyrrolidin-2-yl, L₁     is methyl, and R_(a) is H; (2S) -   a compound of Formula (I) wherein R₁ is 5-fluoro-pyridin-3-yl, R₂ is     3-methyl-4-fluoro-phenyl, A-L- is a₁-L₁, a₁ is pyrrolidin-2-yl, L₁     is methyl, and R_(a) is H; (2S) -   a compound of Formula (I) wherein R₁ is 5-cyano-pyridin-3-yl, R₂ is     4-trifluoromethyl-phenyl, A-L- is a₁-L₁, a₁ is pyrrolidin-2-yl, L₁     is methyl, and R_(a) is H; (2S) -   a compound of Formula (I) wherein R₁ is 5-fluoro-pyridin-3-yl, R₂ is     4-trifluoromethyl-phenyl, A-L- is a₁-L₁, a₁ is pyrrolidin-2-yl, L₁     is methyl, and R_(a) is H; (2S) -   a compound of Formula (I) wherein R₁ is 5-fluoro-pyridin-3-yl, R₂ is     4-methanesulfonyl-phenyl, A-L- is a₁-L₁, a₁ is pyrrolidin-2-yl, L₁     is methyl, and R_(a) is H; (2S) -   a compound of Formula (I) wherein R₁ is 5-fluoro-pyridin-3-yl, R₂ is     4-formamido-phenyl, A-L- is a₁-L₁, a₁ is pyrrolidin-2-yl, L₁ is     methyl, and R_(a) is H; (2S) -   a compound of Formula (I) wherein R₁ is pyridin-3-yl, R₂ is     4-methoxy-phenyl, A-L- is a₁-L₁, a₁ is pyrrolidin-3-yl, L₁ is     absent, and R_(a) is H; (3R) -   a compound of Formula (I) wherein R₁ is pyridin-3-yl, R₂ is     4-methoxy-phenyl, A-L- is a₁-L₁, a₁ is piperidin-2-yl, L₁ is methyl,     and R_(a) is H; (2S) -   a compound of Formula (I) wherein R₁ is pyridin-3-yl, R₂ is     4-methoxy-phenyl, A-L- is a₁-L₁, a₁ is azetidin-3-yl, L₁ is absent,     and R_(a) is H; -   a compound of Formula (I) wherein R₁ is 5-cyano-pyridin-3-yl, R₂ is     4-methoxy-phenyl, A-L- is a₁-L₁, a₁ is pyrrolidin-2-yl, L₁ is     methyl, and R_(a) is H; (2S) -   a compound of Formula (I) wherein R₁ is 5-chloro-pyridin-3-yl, R₂ is     2-methyl-phenyl, A-L- is a₁-L₁, a₁ is pyrrolidin-2-yl, L₁ is methyl,     and R_(a) is H; (2S) -   a compound of Formula (I) wherein R₁ is 5-cyano-pyridin-3-yl, R₂ is     3-methylcarbonyloxy-phenyl, A-L- is a₁-L₁, a₁ is pyrrolidin-2-yl, L₁     is methyl, and R_(a) is H; (2S) -   a compound of Formula (I) wherein R₁ is 5-chloro-pyridin-3-yl, R₂ is     2-chloro-phenyl, A-L- is a₁-L₁, a₁ is pyrrolidin-2-yl, L₁ is methyl,     and R_(a) is H; (2S) -   a compound of Formula (I) wherein R₁ is 5-cyano-pyridin-3-yl, R₂ is     2-chloro-phenyl, A-L- is a₁-L₁, a₁ is pyrrolidin-2-yl, L₁ is methyl,     and R_(a) is H; (2S) -   a compound of Formula (I) wherein R₁ is 5-cyano-pyridin-3-yl, R₂ is     3-hydroxy-phenyl, A-L- is a₁-L₁, a₁ is pyrrolidin-2-yl, L₁ is     methyl, and R_(a) is H; (2S) -   a compound of Formula (I) wherein R₁ is 5-methoxy-pyridin-3-yl, R₂     is 2-chloro-phenyl, A-L- is a₁-L₁, a₁ is pyrrolidin-2-yl, L₁ is     methyl, and R_(a) is H; (2S) -   a compound of Formula (I) wherein R₁ is 5-methylthio-pyridin-3-y, R₂     is 2-chloro-phenyl, A-L- is a₁-L₁, a₁ is pyrrolidin-2-yl, L₁ is     methyl, and R_(a) is H; (2S) -   a compound of Formula (I) wherein R₁ is 5-methylthio-pyridin-3-y, R₂     is 4-methoxy-phenyl, A-L- is a₁-L₁, a₁ is 4-fluoro-pyrrolidin-2-yl,     L₁ is methyl, and R_(a) is H; (2S,4R) -   a compound of Formula (I) wherein R₁ is 5-methoxy-pyridin-3-yl, R₂     is 4-methoxy-phenyl, A-L- is a₁-L₁, a₁ is 4-fluoro-pyrrolidin-2-yl,     L₁ is methyl, and R_(a) is H; (2S,4R) -   a compound of Formula (I) wherein R₁ is pyridin-3-yl, R₂ is     4-methoxy-phenyl, A-L- is a₁-L₁, a₁ is piperidin-3-yl, L₁ is absent,     and R_(a) is H; (3S) -   a compound of Formula (I) wherein R₁ is pyridin-3-yl, R₂ is     4-methoxy-phenyl, A-L- is a₁-L₁, a₁ is pyrrolidin-3-yl, L₁ is     absent, and R_(a) is H; (3S) -   a compound of Formula (I) wherein R₁ is 5-methyl-pyridin-3-yl, R₂ is     4-methoxy-phenyl, A-L- is a₁-L₁, a₁ is 4-fluoro-pyrrolidin-2-yl, L₁     is methyl, and R_(a) is H; (2S,4R) -   a compound of Formula (I) wherein R₁ is 5-methyl-pyridin-3-yl, R₂ is     4-methoxy-phenyl, A-L- is a₁-L₁, a₁ is 4-fluoro-pyrrolidin-2-yl, L₁     is methyl, and R_(a) is H; (2S,4S) -   a compound of Formula (I) wherein R₁ is 5-methoxy-pyridin-3-yl, R₂     is 4-methoxy-phenyl, A-L- is a₁-L₁, a₁ is 4-fluoro-pyrrolidin-2-yl,     L₁ is methyl, and R_(a) is H; (2S,4S) -   a compound of Formula (I) wherein R₁ is 5-methylthio-pyridin-3-y, R₂     is 4-(2-methoxy-ethoxy)-phenyl, A-L- is a₁-L₁, a₁ is     pyrrolidin-2-yl, L₁ is methyl, and R_(a) is H; (2S) -   a compound of Formula (I) wherein R₁ is 5-methyl-pyridin-3-yl, R₂ is     4-(2-methoxy-ethoxy)-phenyl, A-L- is a₁-L₁, a₁ is pyrrolidin-2-yl,     L₁ is methyl, and R_(a) is H; (2S) -   a compound of Formula (I) wherein R₁ is 5-methoxy-pyridin-3-yl, R₂     is 4-(2-methoxy-ethoxy)-phenyl, A-L- is a₁-L₁, a₁ is     pyrrolidin-2-yl, L₁ is methyl, and R_(a) is H; (2S) -   a compound of Formula (I) wherein R₁ is pyridin-3-yl, R₂ is     4-(2-methoxy-ethoxy)-phenyl, A-L- is a₁-L₁, a₁ is pyrrolidin-2-yl,     L₁ is methyl, and R_(a) is H; (2S) -   a compound of Formula (I) wherein R₁ is 5-methoxy-pyridin-3-yl, R₂     is 4-methoxy-phenyl, A-L- is a₁-L₁, a₁ is piperidin-3-yl, L₁ is     absent, and R_(a) is H; (3S) -   a compound of Formula (I) wherein R₁ is 5-methoxy-pyridin-3-yl, R₂     is 4-methoxy-phenyl, A-L- is a₁-L₁, a₁ is piperidin-3-yl, L₁ is     absent, and R_(a) is H; (3R) -   a compound of Formula (I) wherein R₁ is 5-methoxy-pyridin-3-yl, R₂     is 4-methoxy-phenyl, A-L- is a₁-L₁, a₁ is piperidin-3-yl, L₁ is     absent, R_(a) is H; (3S) -   a compound of Formula (I) wherein R₁ is 5-methylthio-pyridin-3-y, R₂     is 3-methylcarbonyloxy-phenyl, A-L- is a₁-L₁, a₁ is pyrrolidin-2-yl,     L₁ is methyl, and R_(a) is H; (2S) -   a compound of Formula (I) wherein R₁ is 5-methoxy-pyridin-3-yl, R₂     is 3-hydroxy-phenyl, A-L- is a₁-L₁, a₁ is pyrrolidin-2-yl, L₁ is     methyl, and R_(a) is H; (2S) -   a compound of Formula (I) wherein R₁ is 5-methoxy-pyridin-3-yl, R₂     is 3-methylcarbonyloxy-phenyl, A-L- is a₁-L₁, a₁ is pyrrolidin-2-yl,     L₁ is methyl, and R_(a) is H; (2S) -   a compound of Formula (I) wherein R₁ is 5-methyl-pyridin-3-yl, R₂ is     3-methylcarbonyloxy-phenyl, A-L- is a₁-L₁, a₁ is pyrrolidin-2-yl, L₁     is methyl, and R_(a) is H; (2S) -   a compound of Formula (I) wherein R₁ is 5-methylthio-pyridin-3-y, R₂     is 4-methoxy-phenyl, A-L- is a₁-L₁, a₁ is piperidin-3-yl, L₁ is     absent, and R_(a) is H; (3S) -   a compound of Formula (I) wherein R₁ is 5-methyl-pyridin-3-yl, R₂ is     4-methoxyphenyl, A-L- is a₁-L₁, a₁ is pyrrolidin-2-yl, L₁ is methyl,     and R_(a) is H; (2S) -   a compound of Formula (I) wherein R₁ is 5-methylthiopyridin-3-yl, R₂     is 4-methoxyphenyl, A-L- is a₁-L₁, a₁ is piperidin-3-yl, L₁ is     absent, R_(a) is H; (3R) -   a compound of Formula (I) wherein R₁ is 5-methylthiopyridin-3-yl, R₂     is 4-methoxyphenyl, A-L- is a₁-L₁, a₁ is pyrrolidin-3-yl, L₁ is     absent, R_(a) is H; (3S) -   a compound of Formula (I) wherein R₁ is 5-methoxypyridin-3-yl, R₂ is     4-methoxyphenyl, A-L- is a₁-L₁, a₁ is pyrrolidin-3-yl, L₁ is absent,     R_(a) is H; (3S) -   a compound of Formula (I) wherein R₁ is 5-methyl-pyridin-3-yl, R₂ is     4-methoxyphenyl, A-L- is a₁-L₁, a₁ is pyrrolidin-3-yl, L₁ is absent,     R_(a) is H; (3S) -   a compound of Formula (I) wherein R₁ is 5-methyl-pyridin-3-yl, R₂ is     4-methoxyphenyl, A-L- is a₁-L₁, a₁ is piperidin-3-yl, L₁ is absent,     R_(a) is H; (3R) -   a compound of Formula (I) wherein R₁ is 5-methyl-pyridin-3-yl, R₂ is     4-methoxyphenyl, A-L- is a₁-L₁, a₁ is piperidin-3-yl, L₁ is absent,     R_(a) is H; (3S) -   a compound of Formula (I) wherein R₁ is 5-methyl-pyridin-3-yl, R₂ is     4-fluoromethoxyphenyl, A-L- is a₁-L₁, a₁ is pyrrolidin-2-yl, L₁ is     methyl, and R_(a) is H; (2S) -   a compound of Formula (I) wherein R₁ is pyridin-3-yl, R₂ is     4-methoxyphenyl, A-L- is a₁-L₁, a₁ is piperidin-3-yl, L₁ is absent,     R_(a) is H; (3R) -   a compound of Formula (I) wherein R₁ is     6-fluoro-5-methylpyridin-3-yl, R₂ is 4-methoxyphenyl, A-L- is a₁-L₁,     a₁ is pyrrolidin-2-yl, L₁ is methyl, and R_(a) is H; (2S) -   a compound of Formula (I) wherein R₁ is 2,5-dimethyl-pyridin-3-yl,     R₂ is 4-methoxyphenyl, A-L- is a₁-L₁, a₁ is pyrrolidin-2-yl, L₁ is     methyl, and R_(a) is H; (2S) -   a compound of Formula (I) wherein R₁ is     6′-chloro-3,5′-dimethyl-[2,3′]bipyridinyl-5-yl, R₂ is     4-methoxyphenyl, A-L- is a₁-L₁, a₁ is pyrrolidin-2-yl, L₁ is methyl,     and R_(a) is H; (2S) -   a compound of Formula (I) wherein R₁ is     6-chloro-4-methylpyridin-3-yl, R₂ is 4-methoxyphenyl, A-L- is a₁-L₁,     a₁ is pyrrolidin-2-yl, L₁ is methyl, and R_(a) is H; (2S) -   a compound of Formula (I) wherein R₁ is     6-chloro-5-methyl-pyridin-3-yl, R₂ is 4-methoxyphenyl, A-L- is     a₁-L₁, a₁ is pyrrolidin-2-yl, L₁ is methyl, and R_(a) is H; (2S) -   a compound of Formula (I) wherein R₁ is pyridin-3-yl, R₂ is     4-methoxyphenyl, A-L- is a₁-L₁, a₁ is piperidin-2-yl, L₁ is methyl,     and R_(a) is H; (2R) -   a compound of Formula (I) wherein R₁ is     2-chloro-5-methylpyridin-3-yl, R₂ is 4-methoxyphenyl, A-L- is a₁-L₁,     a₁ is pyrrolidin-2-yl, L₁ is methyl, and R_(a) is H; (2S) -   a compound of Formula (I) wherein R₁ is     5-hydroxymethyl-pyridin-3-yl, R₂ is 4-methoxyphenyl, A-L- is a₁-L₁,     a₁ is pyrrolidin-2-yl, L₁ is methyl, and R_(a) is H; (2S) -   a compound of Formula (I) wherein R₁ is pyridin-3-yl, R₂ is     4-methoxyphenyl, A-L- is a₁-L₁, a₁ is 4-hydroxy-pyrrolidin-2-yl, L₁     is methyl, R_(a) is H; (trans 2S,4R) -   a compound of Formula (I) wherein R₁ is pyridin-3-yl, R₂ is     4-methoxyphenyl, A-L- is a₁-L₁, a₁ is -hydroxypyrrolidin-2-yl, L₁ is     methyl, and R_(a) is H; (cis 2R,4R) -   a compound of Formula (I) wherein R₁ is pyridin-3-yl, R₂ is     4-methoxyphenyl, A-L- is a₁-L₁, a₁ is 4-hydroxy-pyrrolidin-2-yl, L₁     is methyl, and R_(a) is H; (cis 2S,4S) -   a compound of Formula (I) wherein R₁ is 5-methoxypyridin-3-yl, R₂ is     4-methoxyphenyl, A-L- is a₁-L₁, a₁ is 4-hydroxy-pyrrolidin-2-yl, L₁     is methyl, R_(a) is H, (trans 2S,4R) -   a compound of Formula (I) wherein R₁ is 5-methoxypyridin-3-yl, R₂ is     4-methoxyphenyl, A-L- is a₁-L₁, a₁ is 4-hydroxy-pyrrolidin-2-yl, L₁     is methyl, and R_(a) is H; (cis 2R,4R) -   a compound of Formula (I) wherein R₁ is 5-cyano-pyridin-3-yl, R₂ is     4-methoxy-phenyl, A-L- is a₂-L₂, a₂ is morpholin-2-yl, L₂ is methyl,     and R_(a) is H; (racemic) -   a compound of Formula (I) wherein R₁ is 5-fluoro-pyridin-3-yl, R₂ is     4-methoxy-phenyl, A-L- is a₂-L₂, a₂ is morpholin-2-yl, L₂ is methyl,     and R_(a) is H; -   a compound of Formula (I) wherein R₁ is pyrimidin-5-yl, R₂ is     4-methoxy-phenyl, A-L- is a₂-L₂, a₂ is morpholin-2-yl, L₂ is methyl,     and R_(a) is H; -   a compound of Formula (I) wherein R₁ is pyrimidin-5-yl, R₂ is     4-methoxy-phenyl, A-L- is a₂-L₂, a₂ is morpholin-3-yl, L₂ is methyl,     and R_(a) is H; (racemic) -   a compound of Formula (I) wherein R₁ is 5-cyano-pyridin-3-yl, R₂ is     4-methoxy-phenyl, A-L- is a₂-L₂, a₂ is morpholin-3-yl, L₂ is methyl,     and R_(a) is H; (racemic) -   a compound of Formula (I) wherein R₁ is 5-cyano-pyridin-3-yl, R₂ is     4-methoxy-phenyl, A-L- is a₂-L₂, a₂ is morpholin-3-yl, L₂ is methyl,     and R_(a) is H; (3S) -   a compound of Formula (I) wherein R₁ is 5-fluoro-pyridin-3-yl, R₂ is     4-methoxy-phenyl, A-L- is a₂-L₂, a₂ is morpholin-3-yl, L₂ is methyl,     and R_(a) is H; (3S) -   a compound of Formula (I) wherein R₁ is pyridin-3-yl, R₂ is     4-methoxy-phenyl, A-L- is a₂₁₂, a₂ is morpholin-3-yl, L₂ is methyl,     and R_(a) is H; (3S) -   a compound of Formula (I) wherein R₁ is 5-cyano-pyridin-3-yl, R₂ is     4-methoxy-phenyl, A-L- is a₃-L₃, a₃ is imidazol-2-yl, L₃ is methyl,     and R_(a) is H; -   a compound of Formula (I) wherein R₁ is 5-cyano-pyridin-3-yl, R₂ is     4-methoxy-phenyl, A-L- is a₃-L₃, a₃ is 3H-imidazol-4-yl, L₃ is     methyl, and R_(a) is H; -   a compound of Formula (I) wherein R₁ is 5-cyano-pyridin-3-yl, R₂ is     4-methoxy-phenyl, A-L- is a₃-L₃, a₃ is 5-methyl-3H-imidazol-4-yl, L₃     is methyl, R and R_(a) is H; -   a compound of Formula (I) wherein R₁ is 5-cyano-pyridin-3-yl, R₂ is     4-methoxy-phenyl, A-L- is a₃-L₃, a₃ is 3-methyl-3H-imidazol-4-yl, L₃     is methyl, and R_(a) is H; -   a compound of Formula (I) wherein R₁ is 5-cyano-pyridin-3-yl, R₂ is     4-methoxy-phenyl, A-L- is a₃-L₃, a₃ is     2-ethyl-5-methyl-3H-imidazol-4-yl, L₃ is methyl, and R_(a) is H; -   a compound of Formula (I) wherein R₁ is pyridin-3-yl, R₂ is     4-methoxy-phenyl, A-L- is a₃-L₃, a₃ is 3H-imidazol-4-yl, L₃ is     methyl, and R_(a) is H; -   a compound of Formula (I) wherein R₁ is 5-methylthio-pyridin-3-y, R₂     is 4-methoxy-phenyl, A-L- is a₃-L₃, a₃ is 3H-imidazol-4-yl, L₃ is     methyl, and R_(a) is H; -   a compound of Formula (I) wherein R₁ is 5-methoxy-pyridin-3-yl, R₂     is 4-methoxy-phenyl, A-L- is a₃-L₃, a₃ is 3H-imidazol-4-yl, L₃ is     methyl, and R_(a) is H; -   a compound of Formula (I) wherein R₁ is 5-methyl-pyridin-3-yl, R₂ is     4-methoxy-phenyl, A-L- is a₃-L₃, a₃ is 3H-imidazol-4-yl, L₃ is     methyl, and R_(a) is H; -   a compound of Formula (I) wherein R₁ is 5-cyano-pyridin-3-yl, R₂ is     4-methoxy-phenyl, A-L- is a₄-L₄, a₄ is 2-amino, L₄ is propyl, and     R_(a) is H; (2S) -   a compound of Formula (I) wherein R₁ is 5-cyano-pyridin-3-yl, R₂ is     4-methoxy-phenyl, A-L- is a₄-L₄, a₄ is 2-amino, L₄ is ethyl, and     R_(a) is H; -   a compound of Formula (I) wherein R₁ is 5-cyano-pyridin-3-yl, R₂ is     4-methoxy-phenyl, A-L- is a₄-L₄, a₄ is 2-amino, L₄ is     4-methyl-pentyl, and R_(a) is H; (2S) -   a compound of Formula (I) wherein R₁ is pyrimidin-5-yl, R₂ is     4-methoxy-phenyl, A-L- is a₄-L₄, a₄ is 2-amino, L₄ is     4-methyl-pentyl, and R_(a) is H; (2S) -   a compound of Formula (I) wherein R₁ is 5-methyl-pyridin-3-yl, R₂ is     4-methoxyphenyl, A-L- is a₄-L₄, a₄ is 2-amino, L₄ is ethyl, and     R_(a) is H; -   a compound of Formula (I) wherein R₁ is pyridin-3-yl, R₂ is     4-methoxyphenyl, A-L- is a₄-L₄, a₄ is 2-methylamino, L₄ is ethyl,     and R_(a) is H; -   a compound of Formula (I) wherein R₁ is 5-cyano-pyridin-3-yl, R₂ is     4-methoxy-phenyl, A-L- is a₅-L₅, a₅ is cyclohexyl, L₅ is absent, and     R_(a) is H; (cis/trans mixture) -   a compound of Formula (I) wherein R₁ is 5-cyano-pyridin-3-yl, R₂ is     4-methoxy-phenyl, A-L- is a₅-L₅, a₅ is cyclohexyl, L₅ is methyl, and     R_(a) is H; (2S,1R) -   a compound of Formula (I) wherein R₁ is pyrimidin-5-yl, R₂ is     4-methoxy-phenyl, A-L- is a₅-L₅, a₅ is cyclohexyl, L₅ is methyl, and     R_(a) is H; (2S,1R) -   a compound of Formula (I) wherein R₁ is 5-cyano-pyridin-3-yl, R₂ is     4-methoxy-phenyl, A-L- is a₅-L₅, a₅ is cyclobutyl, L₅ is methyl, and     R_(a) is H; (trans) -   a compound of Formula (I) wherein R₁ is pyrimidin-5-yl, R₂ is     4-methoxy-phenyl, A-L- is a₅-L₅, a₅ is cyclobutyl, L₅ is methyl, and     R_(a) is H; (trans) -   a compound of Formula (I) wherein R₁ is 5-cyano-pyridin-3-yl, R₂ is     4-methoxy-phenyl, A-L- is a₅-L₅, a₅ is cyclobutyl, L₅ is absent, and     R_(a) is H; (cis/trans mixture) -   a compound of Formula (I) wherein R₁ is pyrimidin-5-yl, R₂ is     4-methoxy-phenyl, A-L- is a₅-L₅, a₅ is cyclobutyl, L₅ is absent, and     R_(a) is H; (cis/trans mixture) -   a compound of Formula (I) wherein R₁ is pyridin-3-yl, R₂ is     4-methoxy-phenyl, A-L- is a₅-L₅, a₅ is cyclohexyl, L₅ is absent, and     R_(a) is H; (cis) -   a compound of Formula (I) wherein R₁ is pyridin-3-yl, R₂ is     4-methoxy-phenyl, A-L- is a₅-L₅, a₅ is cyclohexyl, L₅ is absent, and     R_(a) is H; (racemic, cis/trans mixture) -   a compound of Formula (I) wherein R₁ is pyridin-3-yl, R₂ is     4-methoxy-phenyl, A-L- is a₅-L₅, a₅ is cyclohexyl, L₅ is absent, and     R_(a) is H; (1RS,3SR racemic cis) -   a compound of Formula (I) wherein R₁ is pyridin-3-yl, R₂ is     4-methoxy-phenyl, A-L- is a₅-L₅, a₅ is cyclohexyl, L₅ is absent, and     R_(a) is H; (1RS,2SR racemic single stereoisomer, unknown cis/trans) -   a compound of Formula (I) wherein R₁ is 5-methoxy-pyridin-3-yl, R₂     is 4-methoxy-phenyl, A-L- is a₅-L₅, a₅ is cyclohexyl, L₅ is absent,     and R_(a) is H; racemic, mixture of cis/trans) -   a compound of Formula (I) wherein R₁ is 5-methylthiopyridin-3-yl, R₂     is 4-methoxyphenyl, A-L- is a₅-L₅, a₅ is cyclohexyl, L₅ is absent,     and R_(a) is H; (racemic, mixture of cis and trans) -   a compound of Formula (I) wherein R₁ is 5-methoxypyridin-3-yl, R₂ is     4-methoxyphenyl, A-L- is a₅-L₅, a₅ is cyclohexyl, L₅ is absent, and     R_(a) is H; (cis 1R,3S) -   a compound of Formula (I) wherein R₁ is 5-methoxypyridin-3-yl, R₂ is     4-methoxyphenyl, A-L- is a₅-L₅, a₅ is cyclohexyl, L₅ is absent,     R_(a) is H; (cis 1S,3R) -   a compound of Formula (I) wherein R₁ is 5-methoxypyridin-3-yl, R₂ is     4-methoxyphenyl, A-L- is a₅-L₅, a₅ is cyclohexyl, L₅ is absent, and     R_(a) is H; (trans, one enantiomer, absolute unknown) -   a compound of Formula (I) wherein R₁ is 5-methoxypyridin-3-yl, R₂ is     4-methoxyphenyl, A-L- is a₅-L₅, a₅ is cyclohexyl, L₅ is absent, and     R_(a) is H; (trans, one enantiomer, absolute unknown) -   a compound of Formula (I) wherein R₁ is 5-methyl-pyridin-3-yl, R₂ is     4-methoxyphenyl, A-L- is a₅-L₅, a₅ is cyclohexyl, L₅ is absent, and     R_(a) is H; (racemic, mixture of cis and trans) -   a compound of Formula (I) wherein R₁ is 5-methylthiopyridin-3-yl, R₂     is 4-methoxyphenyl, A-L- is a₅-L₅, a₅ is cyclohexyl, L₅ is absent,     and R_(a) is H; (cis 1S,3R) -   a compound of Formula (I) wherein R₁ is 5-methylthiopyridin-3-yl, R₂     is 4-methoxyphenyl, A-L- is a₅-L₅, a₅ is cyclohexyl, L₅ is absent,     and R_(a) is H; (cis 1R,3S) -   a compound of Formula (I) wherein R₁ is 5-methylthiopyridin-3-yl, R₂     is 4-methoxyphenyl, A-L- is a₅-L₅, a₅ is cyclohexyl, L₅ is absent,     and R_(a) is H; (trans, one enantiomer, absolute unknown) -   a compound of Formula (I) wherein R₁ is 5-methylthiopyridin-3-yl, R₂     is 4-methoxyphenyl, A-L- is a₅-L₅, a₅ is cyclohexyl, L₅ is absent,     and R_(a) is H; (trans, one enantiomer, absolute unknown) -   a compound of Formula (I) wherein R₁ is pyridin-3-yl, R₂ is     4-cyclopropylphenyl, and A-L- and R_(a) are taken together with the     atoms to which they are attached to form piperazin-1-yl; -   a compound of Formula (I) wherein R₁ is pyridin-3-yl, R₂ is     4-methoxyphenyl, A-L- is a₅-L₅, a₅ is cyclohexyl, L₅ is absent, and     R_(a) is H; (cis 1S,3R) -   a compound of Formula (I) wherein R₁ is pyridin-3-yl, R₂ is     4-methoxyphenyl, A-L- is a₅-L₅, a₅ is cyclohexyl, L₅ is absent, and     R_(a) is H; (cis 1R,3S) -   a compound of Formula (I) wherein R₁ is pyridin-3-yl, R₂ is     4-methoxyphenyl, A-L- is a₅-L₅, a₅ is cyclohexyl, L₅ is absent, and     R_(a) is H; (trans, one enantiomer, absolute unknown) -   a compound of Formula (I) wherein R₁ is phenyl, R₂ is     4-methoxy-phenyl, and A-L- and R_(a) are taken together with the     atoms to which they are attached to form piperazin-1-yl; -   a compound of Formula (I) wherein R₁ is 5-cyano-pyridin-3-yl, R₂ is     4-methoxy-phenyl, and A-L- and R_(a) are taken together with the     atoms to which they are attached to form piperazin-1-yl; -   a compound of Formula (I) wherein R₁ is 5-cyano-pyridin-3-yl, R₂ is     4-methoxy-phenyl, and A-L- and R_(a) are taken together with the     atoms to which they are attached to form 3-aminopyrrolidin-1-yl; -   a compound of Formula (I) wherein R₁ is pyridin-3-yl, R₂ is     4-methoxy-phenyl, and A-L- and R_(a) are taken together with the     atoms to which they are attached to form piperazin-1-yl; -   a compound of Formula (I) wherein R₁ is 5-cyano-pyridin-3-yl, R₂ is     4-methoxy-phenyl, A-L- is, A-L- and R_(a) are taken to form,     3-aminopyrrolidin-1-yl; 3S -   a compound of Formula (I) wherein R₁ is 5-cyano-pyridin-3-yl, R₂ is     4-methoxy-phenyl, and A-L- and R_(a) are taken together with the     atoms to which they are attached to form 3-aminopiperidin-1-yl; (3S) -   a compound of Formula (I) wherein R₁ is 5-cyano-pyridin-3-yl, R₂ is     4-methoxy-phenyl, and A-L- and R_(a) are taken together with the     atoms to which they are attached to form 3-aminopiperidin-1-yl; (3R) -   a compound of Formula (I) wherein R₁ is 5-cyano-pyridin-3-yl, R₂ is     4-methoxy-phenyl, and A-L- and R_(a) are taken together with the     atoms to which they are attached to form 3-aminomethylazetidin-1-yl; -   a compound of Formula (I) wherein R₁ is 5-cyano-pyridin-3-yl, R₂ is     4-methoxy-phenyl, and A-L- and R_(a) are taken together with the     atoms to which they are attached to form     2-aminomethylpyrrolidin-1-yl; (2R) -   a compound of Formula (I) wherein R₁ is 5-cyano-pyridin-3-yl, R₂ is     4-methoxy-phenyl, and A-L- and R_(a) are taken together with the     atoms to which they are attached to form 4-aminopiperidin-1-yl; -   a compound of Formula (I) wherein R₁ is 5-cyano-pyridin-3-yl, R₂ is     4-methoxy-phenyl, and A-L- and R_(a) are taken together with the     atoms to which they are attached to form     2-aminomethylpyrrolidin-1-yl; (2R) -   a compound of Formula (I) wherein R₁ is 5-cyano-pyridin-3-yl, R₂ is     4-methoxy-phenyl, and A-L- and R_(a) are taken together with the     atoms to which they are attached to form 3-oxopiperazin-1-yl; -   a compound of Formula (I) wherein R₁ is pyridin-3-yl, R₂ is     4-methoxy-phenyl, and A-L- and R_(a) are taken together with the     atoms to which they are attached to form [1,4]diazepan-1-yl; -   a compound of Formula (I) wherein R₁ is 5-cyano-pyridin-3-yl, R₂ is     4-methoxy-phenyl, and A-L- and R_(a) are taken together with the     atoms to which they are attached to form 2-oxopiperazin-1-yl; -   a compound of Formula (I) wherein R₁ is 5-cyano-pyridin-3-yl, R₂ is     4-methoxy-phenyl, and A-L- and R_(a) are taken together with the     atoms to which they are attached to form     3,6-diaza-bicyclo[3.1.1]hept-3-ylamino; -   a compound of Formula (I) wherein R₁ is pyridin-3-yl, R₂ is     4-methoxy-phenyl, v 3-aminopyrrolidin-1-yl; (3R) -   a compound of Formula (I) wherein R₁ is pyridin-3-yl, R₂ is     4-methoxy-phenyl, and A-L- and R_(a) are taken together with the     atoms to which they are attached to form 3-amino-azetidin-1-yl; -   a compound of Formula (I) wherein R₁ is 5-methylthio-pyridin-3-y, R₂     is 4-methoxy-phenyl, and A-L- and R_(a) are taken together with the     atoms to which they are attached to form piperazin-1-yl; -   a compound of Formula (I) wherein R₁ is 5-methoxy-pyridin-3-yl, R₂     is 4-methoxy-phenyl, and A-L- and R_(a) are taken together with the     atoms to which they are attached to form piperazin-1-yl; -   a compound of Formula (I) wherein R₁ is 5-cyano-pyridin-3-yl, R₂ is     4-methoxy-phenyl, and A-L- and R_(a) are taken together with the     atoms to which they are attached to form 3-methyl-piperazin-1-yl;     (racemic) -   a compound of Formula (I) wherein R₁ is 5-cyano-pyridin-3-yl, R₂ is     4-methoxy-phenyl, and A-L- and R_(a) are taken together with the     atoms to which they are attached to form 2-methyl-piperazin-1-yl;     (2R) -   a compound of Formula (I) wherein R₁ is 5-cyano-pyridin-3-yl, R₂ is     4-methoxy-phenyl, and A-L- and R_(a) are taken together with the     atoms to which they are attached to form 2-methyl-piperazin-1-yl;     (2S) -   a compound of Formula (I) wherein R₁ is 5-methoxy-pyridin-3-yl, R₂     is 4-methoxy-phenyl, and A-L- and R_(a) are taken together with the     atoms to which they are attached to form [1,4]-diazepan-1-yl; -   a compound of Formula (I) wherein R₁ is 5-methylthiopyridin-3-yl, R₂     is 4-methoxyphenyl, and A-L- and R_(a) are taken together with the     atoms to which they are attached to form [1,4]-diazepan-1-yl; -   a compound of Formula (I) wherein R₁ is 5-methylthiopyridin-3-yl, R₂     is 4-methoxyphenyl, and A-L- and R_(a) are taken together with the     atoms to which they are attached to form 3-amino-pyrrolidin-1-yl;     (3R) -   a compound of Formula (I) wherein R₁ is 5-methoxypyridin-3-yl, R₂ is     4-methoxyphenyl, and A-L- and R_(a) are taken together with the     atoms to which they are attached to form 3-amino-pyrrolidin-1-yl;     (3R) -   a compound of Formula (I) wherein R₁ is 5-methylthiopyridin-3-yl, R₂     is 4-methoxyphenyl, and A-L- and R_(a) are taken together with the     atoms to which they are attached to form     3,3-dimethyl-piperazin-1-yl; -   a compound of Formula (I) wherein R₁ is 5-methyl-pyridin-3-yl, R₂ is     4-methoxyphenyl, and A-L- and R_(a) are taken together with the     atoms to which they are attached to form piperazin-1-yl; -   a compound of Formula (I) wherein R₁ is 5-methyl-pyridin-3-yl, R₂ is     4-methoxyphenyl, and A-L- and R_(a) are taken together with the     atoms to which they are attached to form 3-amino-pyrrolidin-1-yl;     (3R) -   a compound of Formula (I) wherein R₁ is pyridin-3-yl, R₂ is     4-methoxyphenyl, and A-L- and R_(a) are taken together with the     atoms to which they are attached to form 4-methyl-piperazin-1-yl; -   a compound of Formula (I) wherein R₁ is pyridin-3-yl, R₂ is     4-methoxyphenyl, and A-L- and R_(a) are taken together with the     atoms to which they are attached to form 2-methyl-piperazin-1-yl;     (2S) -   a compound of Formula (I) wherein R₁ is pyridin-3-yl, R₂ is     4-methoxyphenyl, and A-L- and R_(a) are taken together with the     atoms to which they are attached to form     3,3-dimethyl-piperazin-1-yl; -   a compound of Formula (I) wherein R₁ is pyridin-3-yl, R₂ is     4-methoxyphenyl, and A-L- and R_(a) are taken together with the     atoms to which they are attached to form 3-methyl-piperazin-1-yl;     (3S) -   a compound of Formula (I) wherein R₁ is pyridin-3-yl, R₂ is     4-methoxyphenyl, and A-L- and R_(a) are taken together with the     atoms to which they are attached to form 3-methyl-piperazin-1-yl;     (3R) -   a compound of Formula (I) wherein R₁ is 5-methyl-pyridin-3-yl, R₂ is     4-methoxyphenyl, and A-L- and R_(a) are taken together with the     atoms to which they are attached to form [1,4]diazepan-1-yl; -   a compound of Formula (I) wherein R₁ is pyridin-3-yl, R₂ is     4-methoxyphenyl, and A-L- and R_(a) are taken together with the     atoms to which they are attached to form     3,5-dimethyl-piperazin-1-yl; (cis) -   a compound of Formula (I) wherein R₁ is 5-methoxypyridin-3-yl, R₂ is     4-methoxyphenyl, and A-L- and R_(a) are taken together with the     atoms to which they are attached to form 2-ethyl-piperazin-1-yl;     (2S) -   a compound of Formula (I) wherein R₁ is 5-methoxypyridin-3-yl, R₂ is     4-methoxyphenyl, and A-L- and R_(a) are taken together with the     atoms to which they are attached to form 3-ethyl-piperazin-1-yl;     (3R).

For use in medicine, salts of compounds of formula (I) refer to non-toxic “pharmaceutically acceptable salts.” Other salts may, however, be useful in the preparation of compounds of formula (I) or of their pharmaceutically acceptable salts thereof. Suitable pharmaceutically acceptable salts of compounds of formula (I) include acid addition salts which can, for example, be formed by mixing a solution of the compound with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, sulfuric acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, citric acid, tartaric acid, carbonic acid or phosphoric acid.

Furthermore, where the compounds of formula (I) carry an acidic moiety, suitable pharmaceutically acceptable salts thereof may include alkali metal salts, e.g., sodium or potassium salts; alkaline earth metal salts, e.g., calcium or magnesium salts; and salts formed with suitable organic ligands, e.g., quaternary ammonium salts. Thus, representative pharmaceutically acceptable salts include the following: acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, calcium edetate, camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate, N-methylglucamine ammonium salt, oleate, pamoate (embonate), palmitate, pantothenate, phosphate/diphosphate, polygalacturonate, salicylate, stearate, sulfate, subacetate, succinate, tannate, tartrate, teoclate, tosylate, triethiodide and valerate.

Representative acids and bases which may be used in the preparation of pharmaceutically acceptable salts include the following: acids including acetic acid, 2,2-dichloroacetic acid, acylated amino acids, adipic acid, alginic acid, ascorbic acid, L-aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, (+)-camphoric acid, camphorsulfonic acid, (+)-(1S)-camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxy-ethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, D-gluconic acid, D-glucoronic acid, L-glutamic acid, α-oxo-glutaric acid, glycolic acid, hippuric acid, hydrobromic acid, hydrochloric acid, (+)-L-lactic acid, (±)-DL-lactic acid, lactobionic acid, maleic acid, (−)-L-malic acid, malonic acid, (±)-DL-mandelic acid, methanesulfonic acid, naphthalene-2-sulfonic acid, naphthalene-1,5-disulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, nitric acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, phosphoric acid, L-pyroglutamic acid, salicylic acid, 4-amino-salicylic acid, sebaic acid, stearic acid, succinic acid, sulfuric acid, tannic acid, (+)-L-tartaric acid, thiocyanic acid, p-toluenesulfonic acid and undecylenic acid;

and bases including ammonia, L-arginine, benethamine, benzathine, calcium hydroxide, choline, deanol, diethanolamine, diethylamine, 2-(diethylamino)-ethanol, ethanolamine, ethylenediamine, N-methyl-glucamine, hydrabamine, 1H-imidazole, L-lysine, magnesium hydroxide, 4-(2-hydroxyethyl)-morpholine, piperazine, potassium hydroxide, 1-(2-hydroxyethyl)-pyrrolidine, sodium hydroxide, triethanolamine, tromethamine and zinc hydroxide.

Embodiments of the present invention include prodrugs of compounds of formula (I). In general, such prodrugs will be functional derivatives of the compounds that are readily convertible in vivo into the required compound. Thus, in the methods of treatment of embodiments of the present invention, the term “administering” encompasses the treatment of the various disorders described with the compound specifically disclosed or with a compound which may not be specifically disclosed, but which converts to the specified compound in vivo after administration to a patient. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in “Design of Prodrugs”, ed. H. Bundgaard, Elsevier, 1985.

Where the compounds according to embodiments of this invention have at least one chiral center, they may accordingly exist as enantiomers. Where the compounds possess two or more chiral centers, they may additionally exist as diastereomers. It is to be understood that all such isomers and mixtures thereof are encompassed within the scope of the present invention. Furthermore, some of the crystalline forms for the compounds may exist as polymorphs and as such are intended to be included in the present invention. In addition, some of the compounds may form solvates with water (i.e., hydrates) or common organic solvents, and such solvates are also intended to be encompassed within the scope of this invention. The skilled artisan will understand that the term compound as used herein, is meant to include solvated compounds of Formula I.

Where the processes for the preparation of the compounds according to certain embodiments of the invention give rise to mixture of stereoisomers, these isomers may be separated by conventional techniques such as preparative chromatography. The compounds may be prepared in racemic form, or individual enantiomers may be prepared either by enantiospecific synthesis or by resolution. The compounds may, for example, be resolved into their component enantiomers by standard techniques, such as the formation of diastereomeric pairs by salt formation with an optically active acid, such as (−)-di-p-toluoyl-d-tartaric acid and/or (+)-di-p-toluoyl-l-tartaric acid followed by fractional crystallization and regeneration of the free base. The compounds may also be resolved by formation of diastereomeric esters or amides, followed by chromatographic separation and removal of the chiral auxiliary. Alternatively, the compounds may be resolved using a chiral HPLC column.

One embodiment of the present invention is directed to a composition comprising the (+)-enantiomer of a compound of formula (I) wherein said composition is substantially free from the (−)-isomer of said compound. In the present context, substantially free means less than 25%, preferably less than 10%, more preferably less than 5%, even more preferably less than 2% and even more preferably less than 1% of the (−)-isomer calculated as.

${\% ( + )\text{-}{enantiomer}} = {\frac{\left( {{{mass}( + )}\text{-}{enantiomer}} \right)}{\left( {{{mass}( + )}\text{-}{enantiomer}} \right) + \left( {{{mass}( - )}\text{-}{enantiomer}} \right)} \times 100}$

Another embodiment of the present invention is a composition comprising the (−)-enantiomer of a compound of formula (I) wherein said composition is substantially free from the (+)-isomer of said compound. In the present context, substantially free from means less than 25%, preferably less than 10%, more preferably less than 5%, even more preferably less than 2% and even more preferably less than 1% of the (+)-isomer calculated as

${\% ( - )\text{-}{enantiomer}} = {\frac{\left( {{{mass}( - )}\text{-}{enantiomer}} \right)}{\left( {{{mass}( + )}\text{-}{enantiomer}} \right) + \left( {{{mass}( - )}\text{-}{enantiomer}} \right)} \times 100.}$

During any of the processes for preparation of the compounds of embodiments of the present invention, it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This may be achieved by means of conventional protecting groups, such as those described in Protective Groups in Organic Chemistry, ed. J. F. W. McOmie, Plenum Press, 1973; and T. W. Greene & P. G. M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991. The protecting groups may be removed at a convenient subsequent stage using methods known from the art.

Even though the compounds of embodiments of the present invention (including their pharmaceutically acceptable salts and pharmaceutically acceptable solvates) can be administered alone, they will generally be administered in admixture with a pharmaceutical carrier, excipient or diluent selected with regard to the intended route of administration and standard pharmaceutical practice. Thus, particular embodiments of the present invention are directed to pharmaceutical compositions comprising compounds of formula (I) and one or more than one pharmaceutically acceptable carrier, excipient or diluent.

By way of example, in the pharmaceutical and veterinary compositions of embodiments of the present invention, the compounds of formula (I) may be admixed with any suitable binder(s), lubricant(s), suspending agent(s), coating agent(s), and/or solubilizing agent(s).

Tablets or capsules of the compounds may be administered one or two or more at a time, as appropriate. It is also possible to administer the compounds in sustained release formulations.

Alternatively, compounds of formula (I) can be administered by inhalation (intratracheal or intranasal) or in the form of a suppository or pessary, or they may be applied topically in the form of a lotion, solution, cream, ointment or dusting powder. For example, they can be incorporated into a cream consisting of an aqueous emulsion of polyethylene glycols or liquid paraffin. They can also be incorporated, at a concentration of between 1% and 10% by weight, into an ointment consisting of a white wax or white soft paraffin base together with such stabilizers and preservatives as may be required. An alternative means of transdermal administration is by use of a skin patch.

For some applications, preferably the compositions are administered orally in the form of tablets containing excipients such as starch or lactose, or in capsules or ovules either alone or in admixture with excipients, or in the form of elixirs, solutions or suspensions containing flavoring or coloring agents.

The compositions (as well as the compounds alone) can also be injected parenterally, for example intracavernosally, intravenously, intramuscularly, subcutaneously, intradermally or intrathecally. In this case, the compositions will comprise a suitable carrier or diluent.

For parenteral administration, the compositions are best used in the form of a sterile aqueous solution which may contain other substances, for example, enough salts or monosaccharides to make the solution isotonic with blood.

For buccal or sublingual administration, the compositions may be administered in the form of tablets or lozenges, which can be formulated in a conventional manner.

By way of further example, pharmaceutical and veterinary compositions containing one or more of the compounds of formula (I) as the active ingredient can be prepared by intimately mixing the compound or compounds with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. The carrier may take a wide variety of forms depending upon the desired route of administration (e.g., oral, parenteral, etc.). Thus for liquid oral preparations such as suspensions, elixirs and solutions, suitable carriers and additives include water, glycols, oils, alcohols, flavoring agents, preservatives, stabilizers, coloring agents and the like; for solid oral preparations, such as powders, capsules and tablets, suitable carriers and additives include starches, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents and the like. Solid oral preparations also may be coated with substances such as sugars or be enterically-coated so as to modulate the major site of absorption. For parenteral administration, the carrier will usually consist of sterile water, and other ingredients may be added to increase solubility or preservation. Injectable suspensions or solutions may also be prepared utilizing aqueous carriers along with appropriate additives.

A therapeutically effective amount of compounds of formula (I) or a pharmaceutical composition thereof comprises a dose range from about 0.1 mg to about 3000 mg, in particular from about 1 mg to about 1000 mg or, more particularly, from about 10 mg to about 500 mg of active ingredient in a regimen of about 1 to 4 times per day for an average (70 kg) human; although, it is apparent to one skilled in the art that the therapeutically effective amount for active compounds of the invention will vary as will the conditions being treated.

For oral administration, a pharmaceutical composition is preferably provided in the form of tablets containing 0.01, 10.0, 50.0, 100, 150, 200, 250, and 500 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the subject to be treated.

Advantageously, compounds of formula (I) may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three or four times daily. Furthermore, compounds of formula (I) can be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal skin patches well known to those skilled in that art.

It is also apparent to one skilled in the art that the therapeutically effective dose for active compounds of formula (I) or a pharmaceutical composition thereof will vary according to the desired effect. Therefore, optimal dosages to be administered may be readily determined and will vary with the particular compound used, the mode of administration, the strength of the preparation, and the advancement of the disease condition. In addition, factors associated with the particular subject being treated, including subject age, weight, diet and time of administration, will result in the need to adjust the dose to achieve an appropriate therapeutic level. The above dosages are thus exemplary of the average case. There can be, of course, individual instances wherein higher or lower dosage ranges are merited, and such are within the scope of this invention.

Compounds of formula (I) may be administered in any of the foregoing compositions and dosage regimens or by means of those compositions and dosage regimens established in the art whenever use of the compounds of formula (I) as analgesics is required for a subject in need thereof.

Examples of pain intended to be within the scope of the present invention include, but are not limited to, inflammatory pain, centrally mediated pain, peripherally mediated pain, visceral pain, structural or soft tissue injury related pain, progressive disease related pain, neuropathic pain and acute pain such as caused by acute injury, trauma or surgery and chronic pain such as headache and that caused by neuropathic conditions, post-stroke conditions, cancer, and migraine.

Compounds of the present invention are also useful as immunosuppressants, antiinflammatory agents, agents for the treatment and prevention of neurological and psychiatric conditions, for instance, depression and Parkinson's disease, agents for the treatment of urological and reproductive conditions, for instance, urinary incontinence and premature ejaculation, medicaments for drug and alcohol abuse, agents for treating gastritis and diarrhea, cardiovascular agents and cardioprotective agents and agents for the treatment of respiratory diseases.

The compounds of the present invention are also useful in treating pain caused by osteoarthritis, rheumatoid arthritis, fibromyalgia, migraine, headache, toothache, burn, sunburn, snake bite (in particular, venomous snake bite), spider bite, insect sting, neurogenic bladder, benign prostatic hypertrophy, interstitial cystitis, rhinitis, contact dermatitis/hypersensitivity, itch, eczema, pharyngitis, mucositis, enteritis, cellulites, causalgia, sciatic neuritis, mandibular joint neuralgia, peripheral neuritis, polyneuritis, stump pain, phantom limb pain, post-operative ileus, cholecystitis, postmastectomy pain syndrome, oral neuropathic pain, Charcot's pain, reflex sympathetic dystrophy, Guillain-Barre syndrome, meralgia paresthetica, burning-mouth syndrome, cluster headache, migraine headache, peripheral neuropathy, bilateral peripheral neuropathy, diabetic neuropathy, optic neuritis, postfebrile neuritis, migrating neuritis, segmental neuritis, Gombault's neuritis, neuronitis, cervicobrachial neuralgia, cranial neuralgia, geniculate neuralgia, glossopharyngial neuralgia, migrainous neuralgia, idiopathic neuralgia, intercostals neuralgia, mammary neuralgia, Morton's neuralgia, nasociliary neuralgia, occipital neuralgia, red neuralgia, Sluder's neuralgia, splenopalatine neuralgia, supraorbital neuralgia, vidian neuralgia, inflammatory bowel disease, irritable bowel syndrome, sinus headache, tension headache, labor, childbirth, menstrual cramps, and cancer.

In regard to the use of the present compounds in treatment of the disases or conditions such as those listed above, a therapeutically effective dose can be determined by persons skilled in the art by the use of established animal models. The therapeutically effective dose of the compounds of Formula (I) exemplified in such a treatment is from about 0.001 mg/kg/day to about 300 mg/kg/day. Particularly, the range is from about 0.5 to about 5.0 mg/kg of body weight per day; and more particularly, from about 1.0 to about 3.0 mg/kg of body weight per day. The compounds may be administered on a regimen of 1 to 4 times per day.

General Synthetic Methods

Representative compounds of the present invention can be synthesized in accordance with the general synthetic methods described below and illustrated in the schemes and examples that follow. Since the schemes are an illustration, the invention should not be construed as being limited by the chemical reactions and conditions described in the schemes. The various starting materials used in the schemes and examples are commercially available or may be prepared by methods well within the skill of persons versed in the art. The variables are as defined herein.

Abbreviations used in the instant specification, particularly the schemes and examples, are as follows:

-   -   AcCl acetyl chloride     -   AcOH glacial acetic acid     -   aq. aqueous     -   Bn or Bzl benzyl     -   conc. concentrated     -   DBU 1,8-diazabicyclo[5.4.0]undec-7-ene     -   DCM dichloromethane     -   DMF N,N-dimethylformamide     -   DMSO dimethylsulfoxide     -   dppf 1,1′-bis(diphenylphosphino)ferrocene     -   ESI electron-spray ionization     -   EtOAc ethyl acetate     -   EtOH ethanol     -   h or hrs hour(s)     -   HATU         O-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyl-uronium-hexafluorophosphate     -   HPLC high performance liquid chromatography     -   Me methyl     -   MeOH methanol     -   MHz megahertz     -   min minutes     -   MPLC medium pressure liquid chromatography     -   MS mass spectroscopy     -   NMR nuclear magnetic resonance     -   NT not tested     -   Ph phenyl     -   Pd/C palladium on activated carbon     -   Ph₃P triphenylphosphine     -   PPA polyphosphoric acid     -   rt room temperature     -   TBDMS tetra-butyldimethylsilane     -   TEN Et₃N triethylamine     -   TFA trifluoroacetic acid     -   THF tetrahydrofuran     -   TLC thin layer chromatography     -   TMS tetramethylsilane or tetramethylsilyl

Scheme A illustrates a route for the synthesis of compounds of Formula (I)-A wherein A-L is a₁-L₁- or a₂-L₂-.

The compound of formula A1 is either commercially available or can be made by known methods, including those described in the scientific literature. A compound of formula A1 may be treated with a compound of formula A2 under basic conditions to afford a compound of formula A3. The nitro group of a compound of formula A3 may be reduced to its corresponding primary amino group of formula A4 by the action of a reducing agent such as zinc, tin, or iron in acetic acid, or by catalytic hydrogenation. The resultant amino group of a compound of formula A4 may undergo a reductive alkylation with an amino-protected aldehyde (R is H) or ketone (R is methyl) of formula A5 (wherein P is an amino protecting group) in the presence of a hydride source such as triacetoxysodium borohydride to install the A-L- portion of compounds of the present invention. A compound of formula A6 may be coupled with an R₁-substituted boronic acid of formula A7 in the presence of a transition metal catalyst such as Pd(dppf)Cl₂ and a base such as potassium carbonate to afford a compound of formula A8. Similarly, R₁ substituents may be installed under conventional Stille coupling conditions using appropriately substituted tin reagents. The amine of a compound of formula A8 may be deprotected under appropriate conditions known to those skilled in the art to afford a compound of formula (I)-A of the present invention. For example, Boc-protected amines may be deprotected under acidic conditions using reagents such as HCl, TFA, and the like. Likewise, Cbz-protected amines may be deprotected under acidic conditions or by catalytic hydrogenation.

Scheme B illustrates a route for the synthesis of compounds of Formula (I)-B wherein A-L is a₁-L₁- or a₃-L₃- and L is absent.

Compounds of formula B1 are either commercially available or can be made by known methods including those described in the scientific literature. A ketone of formula B1 wherein the A-ring is a₁ or a₃ may be reacted with a compound of formula A4 using the methods described in Scheme A to afford a compound of formula B2.

Scheme C illustrates a route for the synthesis of certain A-L- intermediates useful toward compounds of the present invention wherein A-L- is a₃-L₃- and L₃ is C₁₋₂alkyl.

Compounds of formula C1 are either commercially available or can be made by known methods described in the scientific literature. A compound of formula C1 (P is an amino protecting group), wherein the A-ring is C₃₋₇cycloalkyl, may be oxidized using an oxidant such as Dess-Martin reagent to afford its corresponding aldehyde of formula C2. Compounds of formula C2 may be used in an analogous manner to a compound of formula A5 in Scheme A.

Scheme D illustrates a route for the synthesis of compounds of formula (I)-D wherein R₁ is 4H-[1,2,4]oxadiazol-5-on-yl.

A compound of formula A6 may be converted to its corresponding cyanide of formula D1 by the action of zinc(II)cyanide in the presence of a palladium catalyst and DMF. Subsequent treatment of a compound of formula D1 with hydroxylamine under of microwave irradiation affords a compound of formula D2. A compound of formula D2 may be converted to a compound of formula D3 via condensation with CDI in the presence of an appropriate coupling agent such as DBU and the like. Deprotection of the amino functionality using conventional chemistry affords compounds of formula (I)-D.

Scheme E illustrates a route for the synthesis of compounds of formula (I)-E wherein R_(a) is C₁₋₄alkylcarbonyl.

A compound of formula A8 may by acylated by the action of a suitable acylating agent, such as an acid chloride, anhydride, or the like to afford a compound of formula E1. Amino deprotection by the standard methods discussed herein affords a compound of formula (I)-E.

Scheme F illustrates a route for the synthesis of compounds of formula (I)-F wherein R₂ is phenyl substituted with amino or a derivative thereof.

The compounds of formula F1 can be made in an analogous manner to a compound of formula A4 together with known methods described in the scientific literature. A compound of formula F1 may be converted to a compound of formula F2 via the synthetic sequences presented in Scheme A. The Cbz-amino protecting group may be removed with palladium catalyzed hydrogenation to afford the corresponding primary amino compound of formula F3. At this stage, the amino group may be treated with a variety of electrophilic reagents to afford desirable R₂ substitutions of the present invention. For example, treatment with a C₁₋₄alkylsulfonyl chloride affords a compound of formula (I)-F. Likewise, the amino group of F3 may be acylated using conventional acylating agents or treated with an alkylating agent to make additional amino derivatives.

Scheme G illustrates an alternate route for the synthesis of intermediates of formula A8.

Compounds of formula G1 are either commercially available or can be made by known methods described in the scientific literature. A compound of formula G1 may be condensed with a compound of formula G2 in the presence of alkoxide to afford a pyrimidine of formula G3. The hydroxy group may be converted to its corresponding chloride of formula G4 by the action of a chlorinating agent such as thionyl chloride, phosphorus trichloride, or the like. Nucleophilic addition of a compound of formula A2 affords a compound of formula G5, which may be saponified by treatment with hydroxide to afford a carboxylic acid of formula G6. Treatment with diphenylphosphorylazide in t-butanol leads to a Curtius arrangement to afford a Boc-protected amine of formula G7. Removal of the Boc protecting group provides the amine of formula G8 which may subsequently undergo a reductive alkylation with a compound of formula A5 to afford a compound of formula A8.

Scheme H illustrates a route for the synthesis of intermediates of formula H5 that may be useful for the preparation of compounds of formula (I) wherein R₂ is di(C₁₋₄alkyl)aminocarbonyl-substituted phenyl.

Compounds of formula H1 are either commercially available or can be made by known methods described in the scientific literature. A compound of formula I1 may be coupled with an appropriately substituted amine in the presence of a suitable coupling agent such as HATU to afford an amide of formula H2. Upon conventional deprotection of the phenolic group, a compound of formula H3 may be reacted with a compound of formula G4 to afford a compound of formula H4 wherein R₂ is an aminocarbonyl-substituted phenyl ring. In a manner analogous to that of intermediate G5, a compound of formula H4 may be converted to a desired compound of formula H5 using the methods of Scheme G.

Scheme I illustrates a route for the preparation of compounds of Formulae-I2, I3, and I4 wherein R₂ is phenyl substituted with hydroxy(C₁₋₄)alkyl, fluoro(C₁₋₄)alkyl, or pyridinyl(C₁₋₄)alkyl, respectively.

A compound of formula I1 may be prepared according to the methods taught herein using conventional reagents. A compound of formula I1 may be coupled with a compound of formula A7 as described herein to afford an R₁-substituted compound of formula I2. A compound of formula I2 may be treated with appropriate reagents to afford amino-deprotected compounds of Formula (I) wherein R₂ is phenyl substituted with hydroxy(C₁₋₄)alkyl. A compound of formula I2 may be converted to a fluoro-alkyl substituted compound of formula I3 by the action of DAST. Subsequent removal of protecting group P affords desired compounds of Formula (I) wherein R₂ is phenyl substituted with fluoroC₁₋₄)alkyl.

Furthermore, a compound of formula I3 may undergo a palladium-catalyzed cross coupling reaction with a pyridine boronic acid to afford compounds of formula I4, which upon removal of protecting group P result in compounds of Formula (I) wherein R₂ is phenyl substituted with pyridinyl(C₁₋₄alkyl.

Scheme J illustrates a route for the preparation of compounds of formula (I)-J wherein A-L- is taken with R_(a) and the nitrogen atom to which they are both attached to form a nitrogen-bound heterocyclyl as defined herein.

Commercially available 2,4-dichloro-5-bromo-pyrimidine may be treated with HBr solution under acidic conditions to form 2,4,5-tribromo-pyrimidine, which may then be reacted with a compound of formula A2 to afford a compound of formula J1. A compound of formula J1 may undergo a palladium catalyzed substitution with a compound of formula A7 under conditions described herein to afford a compound of formula J2. A compound of formula J2 may undergo a second palladium catalyzed substitution with an amino-containing heterocycle (Het), as defined herein, to afford a compound of Formula (I)-J.

Scheme K illustrates a route for the preparation of compounds of formula (I)-K wherein A-L- is a₃-L₃ and L₃ is absent.

A compound mixture of formula K1 is either commercially available or can be made by known methods described in the scientific literature. The free amine of a compound of formula K1 may be Cbz-protected using conventional synthetic methods and subsequently separated into its diastereomeric pairs, of formulae K2-a and K2-b, using normal phase column chromatography. A diastereomeric pair of formula K2-a may be further separated into its individual enantiomers, K2-a1 and K2-a2, using chiral column chromatography. At this stage, each enantiomer (a compound of formula K2-a1 is illustrated) may be Cbz-deprotected using standard palladium catalyzed hydrogenation to afford a compound of formula K3. A compound of formula K3 may be coupled with a compound of formula J2 as described herein to afford a compound of formula K4 which, upon deprotection of its amino group, affords a compound of formula (I)-K.

SPECIFIC EXAMPLES

Reagents were purchased from commercial sources. Nuclear magnetic resonance (NMR) spectra for hydrogen atoms were measured in the indicated solvent with tetramethylsilane (TMS) as the internal standard on a Bruker Avance or Varian (300 or 400 MHz) spectrometer. The values are expressed in parts per million downfield from TMS. The mass spectra (MS) were determined on a Micromass Platform LC or Agilent 1100 LCMS spectrometer as (ESI) m/z (M+H⁺) using an electrospray technique. Microwave accelerated reactions were performed using a CEM Discover or Biotage microwave instrument, and were contained in a sealed pressure vessel unless otherwise noted. Stereoisomeric compounds may be characterized as racemic mixtures or as separate diastereomers and enantiomers thereof using X-ray crystallography and other methods known to one skilled in the art. Unless otherwise noted, the materials used in the examples were obtained from readily available commercial suppliers or synthesized by standard methods known to one skilled in the art of chemical synthesis. The substituent groups, which vary between examples, are hydrogen unless otherwise noted.

Example 1

A. 2-Chloro-4-(4-methoxy-phenoxy)-5-nitro-pyrimidine (1b)

To a solution of 2,4-dichloro-5-nitro-pyrimidine (Compound 1a) (5.82 g; 30.0 mmol) in acetone (480 mL), cooled to 0° C., was added a solution of 4-methoxy-phenol (3.75 g; 30.0 mmol) in a mixture of 1 N NaHCO_(3(aq)) (30 mL) and H₂O (120 mL) dropwise by an addition funnel. After completion of addition, the reaction mixture was allowed to warm to ambient temperature, and was then stirred at room temperature for 3 h. The resultant mixture was evaporated in vacuo, and the residue was washed sequentially with EtOAc, 1 N NaOH_((aq)), and H₂O. The organic phase was washed sequentially with H₂O and brine, and dried over Na₂SO₄. The mixture was filtered and the solvent was evaporated under reduced pressure to give the crude material. The crude material was recrystallized from Et₂O-hexanes to afford Compound 1b (7.70 g; 91% yield) as a yellow solid. ¹H-NMR (400 MHz, CDCl₃): δ 9.17 (s, 1H), 7.13-7.15 (m, 2H), 6.98-7.01 (m, 2H), 3.87 (s, 3H); MS: m/z 282.0 (M+H)⁺.

B. 2-Chloro-4-(4-methoxy-phenoxy)-pyrimidin-5-ylamine (1c)

To a stirred solution of Compound 1b (7.72 g; 27.4 mmol) in a mixture of glacial acetic acid (60 mL) and MeOH (120 mL) was added zinc dust (5.38 g; 82.2 mol) in portions at ambient temperature. The reaction mixture was stirred at room temperature for 20 h. The resultant mixture was filtered through a microglass filter and the filtrate was neutralized to pH 7 with 2 N KOH_((aq)). The mixture was partitioned between CH₂Cl₂ and H₂O. The organic phase was washed sequentially with H₂O and brine, and dried over Na₂SO₄. The mixture was filtered and the solvent was removed under reduced pressure to give the crude material. The crude material was purified by flash column chromatography (SiO₂), eluting with a heptane-EtOAc gradient to afford Compound 1c (5.52 g; 80% yield) as an orange-red solid. ¹H-NMR (400 MHz, CDCl₃): δ 7.94 (s, 1H), 7.12-7.14 (m, 2H), 6.95-6.97 (m, 2H), 3.85 (s, 3H); MS: m/z 252.0 (M+H)⁺.

C. 2-(S)-{[2-Chloro-4-(4-methoxy-phenoxy)-pyrimidin-5-ylamino]-methyl}-pyrrolidine-1-carboxylic acid tert-butyl ester (1e)

To a solution of Compound 1c (4.45 g, 17.7 mmol) in 1,2-dichloroethane (80 mL) was added Boc-L-prolinal (Compound 1d) (5.0 g; 24.4 mmol) and glacial acetic acid (4.5 mL) at ambient temperature, and the mixture was stirred under a nitrogen atmosphere for 3 h. The mixture was then treated with NaB(OAc)₃H (9.37 g; 44.2 mmol) and continually stirred at room temperature for 20 h. The resultant mixture was diluted with CH₂Cl₂, and washed with saturated NaHCO_(3(aq)) and H₂O. The organic phase was washed sequentially with H₂O and brine, and then dried over Na₂SO₄. The mixture was filtered and the filtrate was evaporated under reduced pressure to give the crude material. The crude material was purified by flash column chromatography (SiO₂), eluting with a Et₂O—CH₂Cl₂ gradient to afford Compound 1e (6.54 g; 85% yield) as a pale-yellow solid. ¹H-NMR (400 MHz, CDCl₃): δ 7.73-7.79 (m, 1H), 7.07-7.14 (m, 2H), 6.91-6.98 (m, 2H), 5.73 (br. s, 0.6H), 4.77 (br. s, 0.4H), 4.20-4.30 (m, 1H), 3.85 (s, 3H), 3.21-3.58 (m, 4H), 1.81-2.11 (m, 4H), 1.46-1.49 (m, 9H); MS: m/z 435.1 (M+H)⁺.

D. 2-(S)-{[4-(4-Methoxy-phenoxy)-2-(5-methylsulfanyl-pyridin-3-yl)-pyrimidin-5-ylamino]-methyl}-pyrrolidine-1-carboxylic acid tert-butyl ester (1g)

To a teflon-lined septum sealed Schlenk tube, a mixture of Compound 1e (4.0 g; 9.20 mmol), 5-(methylthio)pyridin-3-yl boronic acid (Compound 1f) (2.32 g; 13.7 mmol), K₂CO₃ (2.50 g; 18.1 mmol) and [1,1′-bis(diphenylphosphino)-ferrocene]dichloro-palladium(II) (0.45 g, 0.55 mmol) in a mixture of ethanol (18 mL) and H₂O (4.5 mL) was irradiated in a microwave reactor at 130° C. for 30 min. The resultant mixture was diluted with EtOAc, washed with saturated NH₄Cl_((aq)) and H₂O. The organic phase was washed with H₂O, and then dried over Na₂SO₄. The mixture was filtered and the filtrate was evaporated under reduced pressure to give the crude material. The crude material was purified by flash column chromatography (SiO₂), eluting with a heptane-EtOAc gradient to afford Compound 1g (3.45 g; 72% yield) as pale-yellow solid. ¹H-NMR (400 MHz, CDCl₃): δ 9.00 (s, 1H), 8.40 (d, 1H), 8.21 (s, 1H), 7.99 (br. s, 1H), 7.12-7.18 (m, 2H), 6.93-6.96 (m, 2H), 5.77 (br. s, 0.6H), 4.90 (br. s, 0.4H), 4.22-4.32 (m, 1H), 3.86 (s, 3H), 3.18-3.56 (m, 4H), 2.47 (s, 3H), 1.80-2.15 (m, 4H), 1.46-1.52 (m, 9H); MS: m/z 524.2 (M+H)⁺.

E. Cpd 107: [4-(4-Methoxy-phenoxy)-2-(5-methylsulfanyl-pyridin-3-yl)-pyrimidin-5-yl]-pyrrolidin-2-(S)-ylmethyl-amine

To a solution of Compound 1g (3.45 g; 6.59 mmol) in CH₂Cl₂ (20 mL) was added trifluoroacetic acid (4.9 mL; 66 mmol) at ambient temperature. The reaction mixture was stirred at room temperature for 20 h. The resultant mixture was adjusted to pH 12 with 1 N NaOH_((aq)). The resultant mixture was extracted with CH₂Cl₂ and H₂O. The organic phase was washed with H₂O, and dried over Na₂SO₄. The mixture was then filtered, and the filtrate was concentrated under reduced pressure. The residue was dissolved in CH₂Cl₂ (35 mL), and treated with 1.0 M HCl in Et₂O (6.6 mL; 6.6 mmol) at ambient temperature. The reaction mixture was stirred at room temperature for 20 h. The resultant mixture was concentrated in vacuo, before the residue was taken up in a small portion of MeOH/CH₂Cl₂, and then triturated with Et₂O. A solid was collected by filteration and dried to afford an HCl salt of Compound 107 (2.33 g; 77% yield) as a pale-yellow solid. HCl salt-¹H-NMR (400 MHz, DMSO-d₆): δ 9.06 (br. s, 1H), 8.83 (d, 1H), 8.66 (br. s, 1H), 8.42 (d, 1H), 8.25 (s, 1H), 8.05 (t, 1H), 7.25-7.29 (m, 2H), 7.04-7.09 (m, 2H), 6.36 (t, 1H), 3.83-3.87 (m, 1H), 3.81 (s, 3H), 3.56 (t, 2H), 3.35 (s, 3H), 3.17-3.26 (m, 2H), 2.12-2.18 (m, 1H), 1.87-2.01 (m, 2H), 1.70-1.76 (m, 1H); MS: m/z 424.2 (M+H)⁺.

Following the procedure described above for Example 1 and substituting the appropriate reagents, starting materials and purification methods known to those skilled in the art, the following compounds of the present invention were prepared:

Cpd MS (M + H)⁺ Cpd MS (M + H)⁺ 1 407.2 2 377.0 4 407.0 3 407.0 6 427.0 5 427.0 8 378.2 7 378.2 10 367.2 9 383.0 12 391.0 11 432.0 14 348.0 13 405.0 16 428.2 15 393.0 18 442.2 17 428.2 20 428.1 19 453.2 22 408.1 21 483.2 24 396.2 23 379.1 26 408.2 25 396.1 28 402.1 27 411.1 30 420.1 29 422.2 32 455.1 31 476.2 34 416.2 33 393.1 37 396.2 36 366.2 39 408.2 38 395.1 41 420.1 40 378.2 43 434.1 42 434.1 49 433.0 45 392.1 51 461.1 50 445.0 53 409.1 52 425.1 55 413.1 54 396.1 57 443.1 56 413.1 59 394.2 58 439.0 62 396.1 61 367.2 64 425.1 63 419.1 67 381.1 65 367.2 69 403.1 68 408.1 71 409.2 70 425.1 73 426.1 72 393.1 75 380.2 74 394.2 77 417.1 76 429.1 81 394.2 78 419.1 83 464.2 82 422.1 85 406.2 84 477.1 87 404.2 86 430.0 90 444.0 88 428.0 96 439.0 91 420.2 98 403.0 97 415.0 100 378.2 99 379.2 102 432.0 101 439.2 104 417.2 103 415.0 106 410.2 105 393.2 110 439.0 108 455.0 112 432.0 111 415.0 114 407.2 113 431.2 117 416.2 115 424.2 119 416.2 118 416.2 123 447.2 122 471.2 125 445.2 124 464.0 127 438.2 126 421.2 129 407.0 128 400.0 131 414.2 130 383.0 133 397.2 132 421.2 140 407.2 139 431.2 142 419.1 141 406.2 144 379.2 143 403.2 146 391.2 145 378.2 148 363.2 147 387.2 150 419.1 149 362.2 152 394.2 151 395.2 154 393.2 153 417.2 178 380.2 155 392.2 180 410.2 179 401.2 183 405.2 182 394.2 185 398.2 184 376.2 187 380.2 186 414.0 190 432.0 189 423.2 192 398.2 191 416.0 201 396.2 200 387.2 203 362.2 202 380.2 205 410.2 204 417.2 211 392.2 210 426.2 219 398.2 218 405.2 221 434.2 220 441.2 227 396.0 222 444.1 229 416.0 230 407.0 231 389.0 232 412.0 233 428.0 241 468.0 242 436.0 243 452.0 244 422.0 249 394.2 253 392.0 262 410.0 263 406.0 265 426.0 266 426.0 268 426.0

Cpd 44

The title compound was prepared in an analogous manner to the preparation of Cpd 107 of Example 1, substituting (4-hydroxy-phenyl)-carbamic acid tert-butyl ester for 4-methoxy-phenol in procedure A, and substituting 4-methoxy-pyridin-3-yl boronic acid for 5-(methylthio)pyridin-3-yl boronic acid in procedure D. MS: m/z 393.2 (M+H)⁺.

Cpd 46

The title compound was prepared in an analogous manner to the preparation of Cpd 107 of Example 1, substituting (4-hydroxy-phenyl)-carbamic acid tert-butyl ester for 4-methoxy-phenol in procedure A, and substituting pyridin-3-yl boronic acid for 5-(methylthio)pyridin-3-yl boronic acid in Procedure D. MS: m/z 363.2 (M+H)⁺.

Cpd 60

The title compound was prepared in an analogous manner to the preparation of Cpd 107 of Example 1, substituting 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrimidine-2-carbonitrile for 5-(methylthio)pyridin-3-yl boronic acid in Procedure D. TFA salt-¹H-NMR (400 MHz, DMSO-d₆): δ 8.95 (s, 2H), 8.53 (br. s, 1H), 8.21 (s, 1H), 7.23-7.26 (m, 2H), 7.04-7.07 (m, 2H), 6.23 (t, 1H), 4.36 (q, 2H), 3.81-3.86 (m, 1H), 3.81 (s, 3H), 3.48-3.53 (m, 2H), 3.15-3.26 (m, 2H), 2.10-2.17 (m, 1H), 1.87-2.00 (m, 2H), 1.65-1.74 (m, 1H), 1.32 (t, 3H); MS: m/z 423.1 (M+H)⁺.

Cpd 92

¹H-NMR (400 MHz, CDCl₃) δ 7.92 (1H, s), 7.60 (2H, s), 7.16-7.14 (2H, m), 6.94 (1H, s), 6.90-6.87 (2H, m), 3.86-3.80 (4H, m), 3.61-3.50 (2H, m), 3.29-3.23 (2H, m), 3.20-2.95 (1H, br s), 2.27 (6H, s), 2.14-2.09 (1H, m), 2.03-2.00 (1H, m), 1.95-1.90 (1H, m), 1.79-1.74 (1H, m); MS: m/z 405.2 (M+H)⁺.

Cpd 93

¹H-NMR (400 MHz, CDCl₃) δ 7.90 (1H, s), 7.62-7.60 (1H, m), 7.52-7.51 (1H, m), 7.15-7.13 (2H, m), 6.94-6.91 (2H, m), 6.76-6.74 (1H, m), 5.94 (2H, s), 4.86-4.83 (1H, m), 3.84 (3H, s), 3.68-3.62 (1H, m), 3.42-3.26 (2H, m), 3.12-3.08 (2H, m), 2.10-2.02 (1H, m), 1.97-1.91 (1H, m), 1.89-1.80 (1H, m), 1.69-1.60 (1H, m); MS: m/z 421.2 (M+H)⁺.

Cpd 94

¹H-NMR (400 MHz, CD₃OD) δ 8.12 (1H, s), 7.90-7.89 (2H, m), 7.37-7.36 (1H, m), 7.19-7.17 (2H, m), 7.05-7.03 (2H, m), 4.03-3.94 (1H, m), 3.68-3.56 (2H, m), 3.42-3.32 (2H, m), 3.31-3.29 (1H, m), 2.36-2.28 (1H, m), 2.19-2.05 (2H, m), 1.93-1.81 (1H, m); MS: m/z 445.0 & 447.0 (M+H)⁺.

Cpd 95

¹H-NMR (400 MHz, CDCl₃) δ 9.33 (1H, s), 8.42-8.40 (1H, m), 8.00 (1H, m), 7.64-7.62 (1H, m), 7.16-7.12 (2H, m), 6.98-6.95 (2H, m), 5.94 (2H, s), 5.03-5.01 (1H, m), 3.87 (3H, s), 3.59-3.55 (1H, m), 3.35-3.29 (1H, m), 3.18-3.10 (1H, m), 3.05-2.94 (2H, m), 2.07-1.99 (1H, m), 1.92-1.79 (2H, m), 1.60-1.54 (1H, m); MS: m/z 403.2 (M+H)⁺.

Cpd 121

The title compound was prepared in an analogous manner to the preparation of Cpd 107 of Example 1, substituting 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrimidine-2-carbonitrile for 5-(methylthio)pyridin-3-yl boronic acid and substituting CH₃CN for ethanol in Procedure D. TFA salt-¹H-NMR (400 MHz, CDCl₃): δ 9.33 (s, 2H), 7.98 (s, 1H), 7.09-7.13 (m, 2H), 6.91-6.96 (m, 2H), 5.59 (t, 1H), 3.85-3.88 (m, 1H), 3.85 (s, 3H), 3.60-3.62 (m, 2H), 3.21-3.26 (m, 2H), 2.18-2.24 (m, 1H), 1.95-2.09 (m, 2H), 1.75-1.85 (m, 1H); MS: m/z 404.2 (M+H)⁺.

Cpd 260

The title compound was prepared in an analogous manner the preparation of Cpd 107 of Example 1, substituting 4-fluoromethoxy-phenol¹ for 4-methoxy-phenol in Procedure A, and substituting 5-methylpyridin-3-yl boronic acid for 5-(methylthio)pyridin-3-yl boronic acid in Procedure D. ¹H-NMR (400 MHz, DMSO-d₆): δ 9.36 (br. s, 1H), 9.02 (br. s, 1H), 8.86 (s, 1H), 8.42-8.43 (m, 1H), 8.24-8.28 (m, 1H), 8.16-8.19 (m, 1H), 6.86-7.38 (m, 4H), 6.34-6.43 (m, 1H), 5.85-5.98 (m, 1H), 5.76 (s, 2H), 3.81-4.14 (m, 1H), 3.52-3.61 (m, 2H), 3.15-3.27 (m, 2H), 2.33 (s, 3H), 2.11-2.19 (m, 1H), 1.84-2.03 (m, 2H), 1.63-1.77 (m, 1H); MS: m/z 410.0 (M+H)⁺. ¹4-Fluoromethoxy-phenol was prepared as illustrated in the following synthetic scheme and procedure.

A. 4-Fluoromethoxy-phenol

To a solution of 1-(4-fluoromethoxy-phenyl)-ethanone (1.5 g; 8.9 mmol) in dichloromethane (30 mL) was added mCPBA (4.0 g; 17.8 mmol). The resulting mixture was stirred at room temperature for 4 h, then washed with saturated NaHCO₃ (3×). The organic layer was dried over Na₂SO₄, concentrated under reduced pressure to give the crude material (3.77 g). The crude material (3.77 g) was dissolved in THF/MeOH/H₂O (5/5/5 mL), then treated with LiOH (4.0 g; 108 mmol) at room temperature for 4 h. The reaction mixture was acidified with 2N HCl solution to pH 5. The mixture was extracted with EtOAc (3×). The organic phases were combined, dried over Na₂SO₄ and concentrated under reduced pressure to afford the title compound (1.3 g). This compound was used directly without further purification.

Cpd 264

The title compound was prepared in an analogous manner to the preparation of Cpd 107 of Example 1, substituting 4-chloro-5-methylpyridin-3-yl boronic acid for 5-(methylthio)pyridin-3-yl boronic acid in Procedure D, and the title compound was obtained as a by-product of Cpd 266. ¹H-NMR (400 MHz, DMSO-d₆): δ 9.44 (br. s, 1H), 9.05 (br. s, 1H), 8.96 (d, 1H), 8.46 (d, 1H), 8.27 (s, 1H), 8.23 (d, 1H), 8.04 (d, 1H), 7.27-7.31 (m, 2H), 7.04-7.08 (m, 2H), 6.41 (br. s, 1H), 3.83-3.90 (m, 1H), 3.57-3.94 (m, 2H), 3.15-3.27 (m, 2H), 2.40 (s, 3H), 2.38 (s, 3H), 2.11-2.19 (m, 1H), 1.85-2.03 (m, 2H), 1.67-1.77 (m, 1H); MS: m/z 517.2 (M+H)⁺.

Example 2

A. 4,4-Difluoro-2-(S)-hydroxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (2b)

To a solution of 4,4-difluoro-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (Compound 2a) (1.5 g; 6.0 mmol) in tetrahydrofuran (15 mL) was added borane-dimethylsulfide complex (3.79 mL; 7.58 mmol) dropwise at ambient temperature. The reaction mixture was refluxed for 2 h. The resultant mixture was allowed to cool to room temperature. The mixture was partitioned between EtOAc and H₂O. The organic phase was washed with H₂O, and then dried over Na₂SO₄. The mixture was filtered and the filtrate was evaporated under reduced pressure to give the crude material. The crude material was purified by flash column chromatography (SiO₂), eluting with a heptane-EtOAc gradient to afford Compound 2b (1.2 g; 84% yield) as a colorless oil. ¹H-NMR (400 MHz, CDCl₃): δ4.08-4.23 (m, 2H), 3.61-3.87 (m, 4H), 2.45-2.57 (m, 1H), 2.15 (br.s, 1H), 1.49 (s, 9H).

B. 4,4-Difluoro-2-(S)-formyl-pyrrolidine-1-carboxylic acid tert-butyl ester (2c)

To a solution of Compound 2b (1.33 g; 5.61 mmol) in CH₂Cl₂ (20 mL) was added 3,3,3-triacetoxy-3-iodophthalide (3.56 g; 8.39 mmol) at ambient temperature. The reaction mixture was stirred at room temperature for 2 h. The resultant mixture was diluted with EtOAc, and washed sequentially with saturated NaHCO_(3(aq)) and H₂O. The organic phase was washed with H₂O, and then dried over Na₂SO₄. The mixture was filtered and the filtrate was evaporated under reduced pressure to give the crude material. The crude material was purified by flash column chromatography (SiO₂), eluting with a heptane-EtOAc gradient to afford Compound 2c (0.58 g; 44% yield) as a colorless oil. ¹H-NMR (400 MHz, CDCl₃): δ 9.59 (d, 1H), 4.28-4.45 (m, 1H), 3.77-3.89 (m, 2H), 2.43-2.63 (m, 2H), 1.46-1.51 (m, 9H).

Following the procedure described above for Example 2 and substituting the appropriate starting materials and purification methods known to those skilled in the art, the following aldehydes were prepared:

Example 3

A. 3-Oxo-piperidine-1-carboxylic acid tert-butyl ester (3b)

To a solution of 3-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (Compound 3a) (0.25 g; 1.24 mmol) in anhydrous dichloromethane (9.0 mL) at 0° C. was added 1,1,1-tris(actyloxy)-1,1-dihydro-1,2-benzodioxol-3-(1H)-one (1.58 g; 3.72 mmol). The mixture was allowed to stir at room temperature under nitrogen for 2 h, to which was then added additional 1,1,1-tris(actyloxy)-1,1-dihydro-1,2-benziodoxol-3-(1H)-one (0.5 g; 1.18 mmol). Upon stirring for 20 h at room temperature, the reaction mixture was partitioned between dichloromethane and brine. The organic layer was washed with brine, dried over Na₂SO₄, filtered, and the solvent evaporated in vacuo to yield a crude oil. The crude oil was purified via flash column chromatography, eluting with 40% ethyl acetate in hexanes, to yield Compound 3b as an oil (0.24 g; 97% yield). ¹H NMR (400 MHz, CDCl₃): δ 4.0 (2H, br s), 3.60-3.57 (2H, m), 2.49-2.45 (2H, m), 2.01-1.95 (1H, m), 1.46 (9H, s).

Example 4

A. trans-(3-Formyl-cyclobutyl)-carbamic acid tert-butyl ester (4b)

To a solution of trans-(3-hydroxymethyl-cyclobutyl)-carbamic acid tert-butyl ester (Compound 4a) (0.2 g; 1.0 mmol) in anhydrous dichloromethane (8.0 mL) at 0° C. was added 1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benzodioxol-3-(1H)-one (0.84 g; 2.0 mmol). The reaction was allowed to stir at room temperature under nitrogen for 3 h, before partitioning the reaction mixture between dichloromethane and brine. The organic layer was washed with brine, dried over Na₂SO₄, filtered, and the solvent evaporated in vacuo to yield a crude oil. The crude oil was purified via flash column chromatography, eluting with 30% ethyl acetate in hexanes, to yield Compound 4b as a foam (0.2 g; 88% yield). ¹H NMR (400 MHz, CDCl₃): δ 9.82 (1H, d), 4.77 (1H, br s), 4.16-4.11 (1H, br s), 3.04-3.03 (1H, m), 2.69-2.64 (2H, m), 2.21-2.13 (2H, m), 1.44 (9H, s).

Following the procedure described above for Example 4 and substituting the appropriate starting materials and purification methods known to those skilled in the art, the following aldehydes were prepared:

¹H NMR (400 MHz, CDCl₃): δ 9.58 (1H, d), 4.53 (1H, br s), 3.75 (1H, br s), 2.12-2.0 (2H, m), 1.84-1.73 (2H, m), 1.54-1.15 (13H, m).

¹H NMR (400 MHz, CDCl₃): δ 9.59 (1H, br s), 4.9 (1H, br s), 4.26-4.24 (1H, m), 1.79-1.62 (2H, m), 1.45 (9H, s), 1.44-1.36 (1H, m), 0.98-0.96 (6H, m).

Following the procedure described above for Example 1 and substituting the appropriate reagents, starting materials (including the aldehydes or ketones which were prepared in Examples 2, 3, and 4), and purification methods known to those skilled in the art, the following compounds of the present invention were prepared:

Cpd MS (M + H)⁺ Cpd MS (M + H)⁺ 79 415.2 80 397.1 89 397.2 277 419.2 278 412.2 279 395.2 280 395.2 281 419.2 282 419.1 134 421.0 283 412.2 193 414.2 284 394.2 195 419.2 194 430.0 235 426.0 234 442.0 239 410.0 238 410.0 240 426.0 Additional compounds with NMR data (below table):

Cpd 109

¹H NMR (400 MHz, CDCl₃): δ 9.30 (1H, s), 9.12 (2H, s), 8.07 (1H, s), 7.16-7.13 (2H, m), 6.97-6.95 (2H, m), 4.74-4.72 (1H, m), 3.87 (3H, s), 3.63-3.55 (1H, m), 3.30-3.26 (1, m), 2.95-2.91 (1H, m), 2.81-2.71 (2H, m), 2.05-1.99 (1H, m), 1.84-1.77 (1H, m), 1.68-1.57 (2H, m); MS: m/z 379.2 (M+H)⁺.

Cpd 196

HCl salt-¹H-NMR (400 MHz, DMSO-d₆): δ 9.90 (br, s, 1H), 9.79 (br. s, 1H), 9.06 (d, 1H), 8.59 (dd, 1H), 8.34 (d, 1H), 8.32 (s, 1H), 7.53 (dd, 1H), 7.27-7.32 (m, 2H), 7.04-7.08 (m, 2H), 6.45 (t, 1H), 5.48 (dt, 1H), 4.04-4.11 (m, 1H), 3.81 (s, 3H), 3.42-3.80 (m, 5H), 1.91-2.09 (m, 1H); MS: m/z 396.2 (M+H)⁺.

Cpd 292

¹H NMR (400 MHz, CDCl₃): δ 9.42 (1H, d), 8.76 (1H, d), 8.57 (1H, t), 7.99 (1H, s), 7.15-7.13 (2H, m), 6.98-6.96 (2H, m), 4.98 (1H, t), 3.87 (3H, s), 3.33-3.26 (2H, m), 3.09-3.04 (1H, m), 1.26 (3H, d); MS m/z 377.0 (M+H)⁺.

Cpd 293

¹H NMR (400 MHz, CDCl₃): δ 9.42 (1H, d), 8.76 (1H, d), 8.57 (1H, t), 8.0 (1H, s), 7.15-7.13 (2H, m), 6.98-6.96 (2H, m), 4.93 (1H, t), 3.88 (3H, s), 3.37-3.33 (2H, m), 3.12-3.09 (2H, m); MS: m/z 363.0 (M+H)⁺.

Cpd 294

¹H NMR (400 MHz, CDCl₃): δ 9.42 (1H, d), 8.76 (1H, d), 8.58-8.57 (1H, m), 7.98 (1H, s), 7.16-7.14 (2H, m), 6.98-6.96 (2H, m), 5.0 (1H, br s), 3.87 (3H, s), 3.35-3.30 (1H, m), 3.19-3.14 (1H, m), 3.03-2.97 (1H, m), 1.84-1.77 (1H, m), 1.39-1.36 (2H, m), 1.0-0.95 (6H, dd); MS: m/z 419.2 (M+H)⁺.

Cpd 295

¹H NMR (400 MHz, CDCl₃): δ 9.31 (2H, s), 9.12 (1H, s), 7.99 (1H, s), 7.16-7.14 (2H, m), 6.97-6.94 (2H, m), 5.0 (1H, br s), 3.87 (3H, s), 3.35-3.31 (1H, m), 3.2-3.14 (1H, m), 3.02-2.97 (1H, m), 1.84-1.77 (1H, m), 1.4-1.35 (2H, m), 1.0-0.95 (6H, dd); MS: m/z 395.2 (M+H)⁺.

Cpd 298

¹H NMR (400 MHz, CDCl₃): δ 9.41-9.40 (2H, m), 8.76-8.75 (2H, m), 8.56-8.55 (2H, m), 7.98-7.96 (2H, d), 7.15-7.12 (4H, m), 6.99-6.96 (4H, m), 4.61-4.56 (1H, m), 4.35-4.33 (1H, m), 3.88-3.87 (6H, d), 3.70-3.65 (1H, m), 3.42-3.37 (2H, m), 3.02-2.98 (1H, m), 2.84-2.77 (2H, m), 2.25-2.22 (2H, m), 2.02-1.90 (4H, m), 1.86-1.75 (4H, m), 1.42-1.25 (8H, m); MS: m/z 417.2 (M+H)⁺.

Cpd 299

¹H NMR (400 MHz, CDCl₃): δ 9.41 (1H, d), 8.75 (1H, d), 8.57 (1H, t), 7.99 (1H, s), 7.15-7.13 (2H, m), 6.98-6.96 (2H, m), 6.11 (1H, br s), 3.87 (3H, s), 3.37-3.34 (1H, m), 3.29-3.26 (1H, m), 2.54-2.48 (1H, m), 1.92-1.87 (2H, m), 1.77-1.74 (2H, m), 1.55-1.19 (5H, m); MS: m/z 431.0 (M+H)⁺.

Cpd 300

¹H NMR (400 MHz, CDCl₃): δ 9.31 (2H, s), 9.11 (1H, s), 8.0 (1H, s), 7.15-7.13 (2H, m), 6.96-6.94 (2H, m), 5.98 (1H, br s), 3.86 (3H, s), 3.39-3.34 (1H, m), 3.29-3.25 (1H, m), 2.54-2.48 (1H, m), 1.91-1.88 (2H, m), 1.76-1.74 (2H, m), 1.55-1.19 (5H, m); MS: m/z 407.0 (M+H)⁺.

Cpd 301

¹H NMR (400 MHz, CDCl₃): δ 9.41 (1H, s), 8.76 (1H, s), 8.57 (1H, s), 7.97 (1H, s), 7.14-7.12 (2H, m), 6.98-6.96 (2H, m), 4.43-4.40 (1H, m), 3.87 (3H, s), 3.73-3.69 (1H, br s), 3.36-3.33 (2H, m), 2.61-2.57 (1H, m), 2.30-2.22 (2H, m), 2.01-1.94 (2H, m); MS: m/z 403.2 (M+H)⁺.

Cpd 302

¹H NMR (400 MHz, CDCl₃): δ 9.31 (2H, s), 9.12 (1H, s), 7.98 (1H, s), 7.14-7.12 (2H, m), 6.97-6.94 (2H, m), 4.40-4.37 (1H, m), 3.86 (3H, s), 3.71-3.65 (1H, br s), 3.36-3.32 (2H, m), 2.61-2.57 (1H, m), 2.30-2.22 (2H, m), 2.01-1.93 (2H, m); MS: m/z 379.2 (M+H)⁺.

Cpd 303

¹H NMR (400 MHz, CDCl₃): δ 9.42 (4H, d), 8.76 (2H, d), 8.57-8.56 (2H, m), 7.88 (1H, s), 7.81 (1H, s), 7.15-7.12 (4H, m), 6.99-6.96 (4H, m), 4.63-4.59 (1H, m), 4.19-4.13 (1H, m), 3.88-3.81 (7H, m), 3.69-3.64 (1H, m), 3.38-3.34 (1H, m), 3.00-2.94 (1H, m), 2.39-2.33 (4H, m), 2.30-2.24 (4H, m); MS: m/z 389.2 (M+H)⁺.

Cpd 304

¹H NMR (400 MHz, CDCl₃): δ 9.31 (4H, s), 9.12 (2H, s), 7.88 (1H, s), 7.81 (1H, s), 7.15-7.12 (4H, m), 6.98-6.95 (4H, m), 4.59-4.55 (1H, m), 4.17-4.13 (1H, m), 3.88-3.81 (7H, m), 3.68-3.66 (1H, m), 3.38-3.34 (1H, m), 3.00-2.94 (1H, m), 2.39-2.33 (4H, m), 2.29-2.23 (4H, m); MS: m/z 365.2 (M+H)⁺.

Example 5

A. 5-[5-Amino-4-(4-methoxy-phenoxy)-pyrimidin-2-yl]-nicotinonitrile (5b)

Using an adaptation of the method described in Procedure D of Example 1, substituting Compound 5a for Compound 1f, the title Compound 5b was obtained. MS: m/z 320.1 (M+H)⁺.

B. Cpd 285: 5-{4-(4-Methoxy-phenoxy)-5-[(5-methyl-3H-imidazol-4-ylmethyl)-amino]-pyrimidin-2-yl}-nicotinonitrile

Using an adaptation of the method described in Procedure C of Example 1, substituting Compound 5b for Compound 1c, and substituting 5-methyl-3H-imidazole-4-carbaldehyde for Compound 1d, the title Compound 285 was obtained as a free base. ¹H-NMR (400 MHz, DMSO-d₆): δ 11.79 (br. s, 1H), 9.21 (s, 1H), 8.94 (s, 1H), 8.51 (s, 1H), 8.31 (s, 1H), 7.47 (s, 1H), 7.27 (d, 2H), 7.05 (d, 2H), 6.44 (br. s, 1H), 4.03 (m, 2H), 3.81 (s, 3H), 2.23 (s, 3H); MS: m/z 414.0 (M+H)⁺.

Following the procedure described above for Example 5 and substituting the appropriate reagents, starting materials and purification methods known to those skilled in the art, the following compounds of the present invention were prepared:

Cpd MS (M + H)⁺ Cpd MS (M + H)⁺ 283 400.0 284 400.2 286 414.0 287 442.0 288 375.0 289 421.0 290 405.0 291 389.0

Example 6

A. 2-(S)-{[2-Cyano-4-(4-methoxy-phenoxy)-pyrimidin-5-ylamino]-methyl}-pyrrolidine-1-carboxylic Acid tert-Butyl Ester (6a)

A mixture of Compound 1e (0.4 g; 0.92 mmol), Zn(CN)₂ (0.11 g; 0.92 mmol), and Pd(PPh₃)₄ (0.106 g; 0.092 mmol) in DMF (2.4 mL) was irradiated at 160° C. in a CEM microwave reactor for 16 min. Purification by preparative TLC, eluting with 1/1 EtOAc/hexanes, gave the product 6a (0.059 g; 15% yield). MS: m/z 426.2 (M+H)⁺.

B. 2-(S)-{[2-(N-Hydroxycarbamimidoyl)-4-(4-methoxy-phenoxy)-pyrimidin-5-ylamino]-methyl}-pyrrolidine-1-carboxylic Acid tert-Butyl Ester (6b)

To a microwave vessel was added NaHCO₃ (0.03 g; 0.354 mmol), hydroxylamine hydrochloride (0.016 g; 0.236 mmol) and H₂O (0.2 mL). A suspension of Compound 6a (0.05 g; 0.118 mmol) in EtOH (0.5 mL) was added to the vessel, and the reaction mixture was irradiated at 130° C. in a CEM microwave reactor for 32 min. Purification by preparative TLC, eluting with 1/1 EtOAc/hexanes, gave the product 6b (0.053 g; 98% yield). MS: m/z 456.2 (M+H)⁺.

C. 2-(S)-{[4-(4-Methoxy-phenoxy)-2-(5-oxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl)-pyrimidin-5-ylamino]-methyl}-pyrrolidine-1-carboxylic Acid tert-Butyl Ester (6c)

To a solution of Compound 6b (0.038 g; 0.0828 mmol) and 1,1′-carbonyldiimidazole (0.015 g; 0.091 mmol) in CH₃CN (1 mL) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (0.05 mL, 0.33 mmol) and the resulting mixture was stirred at rt for 20 h. The reaction mixture was washed with water, dried over Na₂SO₄, filtered, and the solvent evaporated in vacuo to yield Compound 6c. MS: m/z 485.3 (M+H)⁺.

D. Cpd 35: 3-{4-(4-Methoxy-phenoxy)-5-[(pyrrolidin-2-(S)-ylmethyl)-amino]-pyrimidin-2-yl}-4H-[1,2,4]oxadiazol-5-one

To a solution of Compound 6c (150 mg; 0.31 mmol) in CH₂Cl₂ (4 mL) was added TFA (1 mL) and the mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated and the resultant residue was purified by reverse phase HPLC to afford Compound 35 as a TFA salt. ¹H-NMR (300 MHz, CD₃OD): δ 8.16 (s, 1H), 7.18 (d, 2H), 7.00 (d, 2H), 3.97 (m, 1H), 3.83 (s, 3H), 3.61-3.66 (m, 2H), 3.34-3.40 (m, 2H), 2.27-2.35 (m, 1H), 2.04-2.19 (m, 2H), 1.82-1.92 (m, 1H); MS: m/z 385.2 (M+H)⁺.

Example 7

A. 2-(S)-{[4-(4-Methoxy-phenoxy)-2′-methylsulfanyl-[2,4]bipyrimidin-yl-5-ylamino]-methyl}-pyrrolidine-1-carboxylic acid tert-butyl ester (7b)

To a teflon-lined septum-sealed Schlenk tube, a mixture of Compound 1e (213 mg; 0.49 mmol), 2-methylsulfanyl-4-tributylstannanyl-pyrimidine (Compound 7a) (305 mg; 0.735 mmol) and tetrakis-(triphenylphosphine)palladium(0) (57 mg; 0.049 mmol) in dioxane (1.0 mL) was irradiated in a Microwave reactor at 150° C. for 30 min. The resultant mixture was diluted with EtOAc, and washed with saturated NH₄Cl_((aq)) and H₂O. The organic phase was washed with H₂O, and then dried over Na₂SO₄. The mixture was filtered and the filtrate was evaporated under reduced pressure to give the crude material. The crude material was purified by flash column chromatography (SiO₂), eluting with a heptane-EtOAc gradient to afford Compound 7b (129 mg; 50% yield). ¹H-NMR (400 MHz, CDCl₃): δ 8.48-8.50 (m, 1H), 8.08-8.12 (m, 1H), 7.54-7.57 (m, 1H), 7.16-7.23 (m, 2H), 6.96-7.01 (m, 2H), 6.27 (br. s, 0.7H), 5.18 (br, 0.3H), 4.25-4.36 (m, 1H), 3.88 (s, 3H), 3.24-3.59 (m, 4H), 2.68 (s, 3H), 1.79-2.16 (m, 4H), 1.44-1.54 (m, 9H); MS: m/z 525.2 (M+H)⁺.

B. Cpd 66: [4-(4-Methoxy-phenoxy)-2′-methylsulfanyl-[2,4]bipyrimidinyl-5-yl]-pyrrolidin-2-(S)-ylmethyl-amine

Using an adaptation of the method described in Procedure E of Example 1, substituting Compound 7b for Compound 1g, the title Compound 66 was obtained as a HCl salt. ¹H-NMR (400 MHz, DMSO-d₆): δ 8.89 (br. s, 1H), 8.62 (d, 1H), 8.31 (s, 1H), 7.59 (d, 1H), 7.29-7.31 (m, 2H), 7.02-7.04 (m, 2H), 6.66 (t, 1H), 3.83 (t, 1H), 3.80 (s, 3H), 3.57-3.60 (m, 2H), 3.11-3.25 (m, 2H), 2.45 (s, 3H), 2.08-2.15 (m, 1H), 1.84-1.99 (m, 2H), 1.66-1.74 (m, 1H); MS: m/z 425.1 (M+H)⁺.

Following the procedure described above for Example 8 and substituting the appropriate reagents, starting materials and purification methods known to those skilled in the art, the following compounds of the present invention were prepared:

Cpd MS (M + H)⁺ Cpd MS (M + H)⁺ 47 434.1 48 384.1 120 379.2

Example 8

A. 2-(S)-{[4-(4-Methoxy-phenoxy)-[2,5′]bipyrimidinyl-5-ylamino]-methyl}-pyrrolidine-1-carboxylic acid tert-butyl ester (8b)

Using an adaptation of the method described in Procedure D of Example 1, substituting pyrimidine-5-boronic acid (Compound 8a) for Compound 1f, the title Compound 8b was obtained as a pale-yellow solid. ¹H-NMR (400 MHz, CDCl₃): δ 9.31 (s, 2H), 9.11 (s, 1H), 8.00-8.03 (m, 1H), 7.10-7.15 (m, 2H), 6.93-6.96 (m, 2H), 5.89 (br. s, 0.7H), 4.98 (br. s, 0.3; H), 4.21-4.35 (m, 1H), 3.86 (s, 3H), 3.19-3.56 (m, 4H), 1.80-2.14 (m, 4H), 1.43-1.46 (m, 9H); MS: m/z 479.2 (M+H)⁺.

B. Cpd 156: 4-{5-[(Pyrrolidin-2-(S)-ylmethyl)-amino]-[2,5]bipyrimidinyl-4-yloxy}-phenol

To a solution of Compound 8b (100 mg; 0.21 mmol) in CH₂Cl₂ (10 mL) cooled to 0° C. was added BBr₃—S(CH₃)₂ in CH₂Cl₂ (1.0 M, 1.5 mL) dropwise. The mixture was allowed to warm to ambient temperature, and then was refluxed at 70° C. for 5 h. An additional portion of BBr₃—S(CH₃)₂ in CH₂Cl₂ (1.0 M, 1.5 mL) was added to the reaction mixture upon reaching room temperature. The reaction mixture was refluxed at 70° C. for 20 h. The reaction was adjusted to pH 6 with 1 N NaOH_((aq)), and the organic phase was concentrated. The resultant residue was purified by reverse phase HPLC, eluting with a CH₃CN—H₂O gradient to afford Compound 156 (29.7 mg; 27% yield) as a HBr salt. ¹H-NMR (400 MHz, DMSO-d₆): δ 9.54 (s, 1H), 9.17 (s, 1H), 9.16 (s, 1H), 8.97 (br. s, 1H), 8.55 (br. s, 1H), 7.27 (d, 1H), 7.12-7.15 (m, 2H), 6.86-6.89 (m, 2H), 6.42 (t, 1H), 3.85 (br. s, 1H), 3.53-3.57 (m, 2H), 3.18-3.26 (m, 2H), 2.11-2.18 (m, 1H), 1.88-1.98 (m, 2H), 1.67-1.72 (m, 1H); MS: m/z 365.1 (M+H)⁺.

Example 9

A. 2-(S)-({Acetyl-[4-(4-methoxy-phenoxy)-[2,5′]bipyrimidinyl-5-yl]-amino}-methyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (9a)

To a solution of Compound 8b (89 mg; 0.19 mmol) in CH₂Cl₂ (7 mL) was added acetyl chloride (0.1 mL) and pyridine (0.1 mL) at ambient temperature. The mixture was stirred at room temperature for 3 h. Diluted the resulted mixture with CH₂Cl₂. The organic phase was washed sequentially with H₂O and brine, and then dried over Na₂SO₄. The mixture was filtered and the filtrate was evaporated under reduced pressure to afford Compound 9a. The crude product was used in the next reaction without further purification. MS: m/z 521.3 (M+H)⁺.

B. Cpd 181: N-[4-(4-Methoxy-phenoxy)-[2,5′]bipyrimidinyl-5-yl]-N-pyrrolidin-2-(S)-ylmethyl-acetamide

To a solution of Compound 9a in CH₂Cl₂ (3 mL) was added trifluoroacetic acid (0.4 mL) at ambient temperature. The mixture was stirred at room temperature for 20 h. The solvent was evaporated under reduced pressure. The crude material was purified by reverse phase HPLC, eluting with a CH₃CN—H₂O gradient to afford Compound 181 (71.1 mg; 71% yield) as a TFA salt. ¹H-NMR (400 MHz, DMSO-d₆): δ 9.34 (s, 1H), 9.32 (s, 2H), 9.09 (br. s, 0.6H), 9.00 (s, 0.4H), 8.99 (s, 1H), 8.42 (br. s, 1H), 7.32 (d, 2H), 7.08 (d, 2H), 4.25-4.31 (m, 0.6H), 4.10-4.13 (m, 0.4H), 3.82 (s, 3H), 3.64-3.79 (m, 2H), 3.17-3.31 (m, 2H), 1.85-2.14 (m, 6H), 1.61-1.68 (m, 1H); MS: m/z 421.2 (M+H)⁺.

Example 10

A. 2-(S)-{[4-(3-Hydroxy-phenoxy)-2-(5-methoxy-pyridin-3-yl)-pyrimidin-5-ylamino]-methyl}-pyrrolidine-1-carbxylic acid tert-butyl ester (10a)

The title compound was prepared in a same manner to Compound 1g in Example 1. Using an adaptation of the method described in Procedure A-D, substituting 3-Hydroxy-phenol for 4-Methoxyphenol in Procedure A and substituting 5-Methoxy-pyridin-3-yl boronic acid for Compound 1f in Procedure D, the title Compound 10a was obtained. MS: m/z 494.2 (M+H)⁺.

B. 2-(S)-{[4-(3-Acetoxy-phenoxy)-2-(5-methoxy-pyridin-3-yl)-pyrimidin-5-ylamino]-methyl}-pyrrolidine-1-carboxylic acid tert-butyl ester (10b)

To a solution of Compound 10a (50 mg; 0.1 mmol) in tetrahydrofuran (5 mL), cooled to ˜78° C., was added acetyl chloride (0.009 mL; 0.12 mmol) and triethylamine (0.035 mL; 0.25 mmol). The mixture was stirred at ˜78° C. for 1 hour. Diluted the resulted mixture with EtOAc and H₂O. The organic phase was washed sequentially with H₂O, and then dried over Na₂SO₄. The mixture was filtered and the filtrate was evaporated under reduced pressure to give the crude material. The crude material was purified by flash column chromatography (SiO₂), eluting with a EtOAc-heptane gradient to afford Compound 10b (43 mg; 80% yield). MS: m/z 536.0 (M+H)⁺.

C. Cpd 250: Acetic acid 3-{2-(5-methoxy-pyridin-3-yl)-5-[(pyrrolidin-2-(S)-ylmethyl)-amino]-pyrimidin-4-yloxy}-phenyl ester

Using an adaptation of the method described in Procedure E of Example 1, substituting Compound 10b for Compound 1g, the title Compound 250 was obtained as a HCl salt. ¹H-NMR (400 MHz, DMSO-d₆): δ 9.67 (br. s, 1H), 9.37 (br. s, 1H), 8.75 (s, 1H), 8.44 (s, 1H), 8.35 (s, 1H), 7.99 (s, 1H), 7.55 (t, 1H), 7.31 (d, 1H), 7.26 (s, 1H), 7.11 (d, 1H), 6.63 (br. s, 1H), 3.88 (s, 3H), 3.84 (m, 1H), 3.62-3.68 (m, 2H), 3.13-3.25 (m, 2H), 2.28 (s, 3H), 2.10-2.18 (m, 1H), 1.85-2.02 (m, 2H), 1.68-1.76 (m, 1H); MS: m/z 436.0 (M+H)⁺.

Following the procedure described above for Example 10 and substituting the appropriate reagents, starting materials and purification methods known to those skilled in the art, the following compounds of the present invention were prepared:

Cpd MS (M + H)⁺ Cpd MS (M + H)⁺ 228 431.0 248 452.0 251 420.0

Example 11

A. [4-(5-Amino-2-chloro-pyrimidin-4-yloxy)-phenyl]-carbamic acid benzyl ester (11a)

The title compound was prepared in a same manner to Compound 1c in Example 1. Using an adaptation of the method described in Procedures A and B, substituting (4-hydroxy-phenyl)-carbamic acid benzyl ester (prepared according to the procedure disclosed in U.S. Pat. No. 3,933,470) for 4-methoxyphenol in Procedure A, the title Compound 11a was obtained. MS: m/z 371.2 (M+H)⁺.

B. [4-(5-Amino-2-pyridin-3-yl-pyrimidin-4-yloxy)-phenyl]-carbamic acid benzyl ester (11b)

To a teflon-lined septum sealed Schlenk tube, a mixture of Compound 11a (1.0 g; 2.7 mmol), pyridin-3-yl boronic acid (0.83 g; 6.75 mmol), Cs₂CO₃ (2.60 g; 8.1 mmol) and [1,1′-Bis(diphenylphosphino)-ferrocene]dichloro-palladium(II) (0.49 g; 0.6 mmol) in a mixture of dioxane (15 mL) and EtOH (1 mL) was irradiated in a microwave reactor at 150° C. for 55 min. The reaction mixture was poured into water, diluted with EtOAc and the solid was collected by filtration. The organic phase was isolated and dried over MgSO₄. and the reaction mixture was concentrated under reduced pressure. The resultant residue was purified by reverse phase HPLC, eluting with a CH₃CN—H₂O (0.5% TFA) gradient to afford Compound 11b (0.72 g; 42% yield based on di-TFA). ¹H-NMR (300 MHz, MeOH-d₄): δ 9.2 (s, 1H), 8.9 (d, 1H), 8.7 (d, 1H), 8.2 (s, 1H), 8.0 (m, 1H), 7.5 (d, 2H), 7.5-7.3 (m, 6H), 7.2 (m, 2H), 5.2 (s, 2H); MS: m/z 414.2 (M+H)⁺.

C. 2-(S)-{[4-(4-Benzyloxycarbonylamino-phenoxy)-2-pyridin-3-yl-pyrimidin-5-ylamino]-methyl}-pyrrolidine-1-carboxylic acid tert-butyl ester (11c)

To a solution of Compound 11b (0.55 g; 1.3 mmol) in 1,2-dichloroethane (25 ml) was added Boc-L-prolinal (0.37 mL; 1.9 mmol). To the reaction mixture was then added NaBH(OAc)₃ (0.4 g; 1.9 mmol) portionwise, and the reaction mixture was continually stirred at room temperature for 5 h. The resultant mixture was diluted with water. After stirring for 10 min the organic phase was isolated, washed with brine, and dried over MgSO₄. The solvent was evaporated in vacuo to afford Compound 11c. The compound was used in the next step without further purification.

D. Cpd 177: (4-{2-Pyridin-3-yl-5-[(pyrrolidin-2-(S)-ylmethyl)-amino]-pyrimidin-4-yloxy}-phenyl)-carbamic acid benzyl ester (11d)

To a solution of Compound 11c (80 mg; 0.13 mmol) in CH₂Cl₂ (3 mL) was added trifluoroacetic acid (0.5 mL). The reaction was stirred at room temperature for 3 h and the solvent was evaporated in vacuo to give a crude residue. The crude material was purified by reverse phase HPLC, eluting with a CH₃CN—H₂O gradient to afford Compound 177 (31.6 mg; 46% yield). ¹H-NMR (300 MHz, MeOH-d₄): δ 8.7 (d, 1H), 8.6 (d, 1H), 8.2 (s, 1H), 7.7 (m, 1H), 7.6 (m, 2H), 7.5-7.25 (m, 7H), 7.2 (m, 2H), 5.2 (s, 2H), 4.0 (m, 1H), 3.7 (m, 2H), 3.5-3.3 (m, 4H), 2.4 (m, 1H), 2.2 (m, 2H) 1.9 (m, 1H); MS: m/z 497.2 (M+H)⁺.

Following the procedure described for Example 11 and substituting the appropriate reagents, starting materials and purification methods known to those skilled in the art, the following compounds of the present invention were prepared:

Cpd MS (M + H)⁺ Cpd MS (M + H)⁺ 188 497.2 197 515.2

Example 12

A. 2-(S)-{[4-(4-Benzyloxycarbonylamino-phenoxy)-2-(5-fluoro-pyridin-3-yl)-pyrimidin-5-ylamino]-methyl}-pyrrolidine-1-carboxylic acid tert-butyl ester (12a)

The title compound was prepared according to the method described for Compound 11c in Example 11. Using an adaptation of the method described in Procedures A-C, substituting 5-fluoro-pyridin-3-yl boronic acid for pyridin-3-yl boronic acid in Procedure B, the title Compound 12a was obtained. MS: m/z 615.2 (M+H)⁺.

B. 2-(S)-{[4-(4-Amino-phenoxy)-2-(5-fluoro-pyridin-3-yl)-pyrimidin-5-ylamino]-methyl}-pyrrolidine-1-carboxylic acid tert-butyl ester (12b)

To a Parr bottle was placed 10% Pd/C (100 mg), Compound 12a (1.2 g; 1.9 mmol) and EtOH (35 mL). The reaction mixture was placed under a 50-psi H₂ atmosphere and the reaction was shaken for 20 h. The catalyst was collected by vacuum filtration and the filtrate was evaporated in vacuo to afford Compound 12b. The compound was used in the next step without further purification. MS: m/z 481.0 (M+H)⁺.

C. Cpd 198: [4-(4-Amino-phenoxy)-2-(5-fluoro-pyridin-3-yl)-pyrimidin-5-yl]-pyrrolidin-2-(S)-ylmethyl-amine

Using an adaptation of the method described in Procedure D of Example 11, substituting Compound 12b for Compound 11c, the title Compound 198 (100% yield based on tri-TFA salt) was obtained. ¹H-NMR (300 MHz, MeOH-d₄): δ 8.8 (s, 1H), 8.3 (s, 1H), 8.2 (s, 1H), 8.0 (m, 1H), 7.6-7.4 (m, 4H), 4.0 (br. m, 1H), 3.6 (m, 2H), 3.5-3.2 (m, 4H), 2.2 (m, 1H), 2.0 (m, 2H), 1.8 (m, 1H); MS: m/z 381.2 (M+H)⁺.

Example 13

A. Cpd 213: N-(4-{2-(5-Fluoro-pyridin-3-yl)-5-[(pyrrolidin-2-(S)-ylmethyl)-amino]-pyrimidin-4-yloxy}-phenyl)-methanesulfonamide

To a solution of Compound 12b (30 mg; 0.062 mmol) and i-Pr₂EtN (0.044 mL; 0.25 mmol) in CH₂Cl₂ (4 mL), cooled to 0° C., was added a solution of mesyl chloride (0.0044 mL; 0.062 mmol) in CH₂Cl₂ (2 mL) over 2 h. The reaction was then allowed to warm to room temperature and stirred at room temperature for 20 h. Water was added and the organic phase was isolated, dried over MgSO₄ and filtered, TFA (0.5 mL) was added to the filtrate. The mixture was stirred at room temperature for 1 h. The solvent was evaporated in vacuo. The residue was purified by reverse phase HPLC, eluting with a CH₃CN—H₂O gradient to afford Compound 213 (3.4 mg; 7% yield). ¹H-NMR (300 MHz, DMSO-d₆): δ 8.9 (m, 1H), 8.6 (d, 1H), 8.45 (m, 1H), 8.3 (m, 2H), 7.7 (d, 2H), 7.5 (m, 1H), 7.25 (d, 2H), 3.85 (m, 1H), 3.5 (m, 2H), 3.2 (m, 2H), 3.1-2.7 (m, 2H), 2.6 (s, 3H), 2.1 (m, 1H), 1.95 (m, 1H), 1.7 (m, 1H); MS: m/z 459.1 (M+H)⁺.

Following the procedure described above for Example 13 and substituting the appropriate reagents, starting materials and purification methods known to those skilled in the art, the following compounds of the present invention were prepared:

Cpd MS (M + H)⁺ Cpd MS (M + H)⁺ 212 423.3 214 441.2 216 391.2 223 409.2

Example 14

A. 4-Hydroxy-2-pyridin-3-yl-pyrimidine-5-carboxylic acid ethyl ester (14c)

A suspension of Compound 14a (6.1 g; 38.64 mmol) in sodium ethoxide solution (21 wt. % in denatured ethanol) (100 mL) was stirred at room temperature for 10 min. To the mixture was added Compound 14b (7.81 mL; 38.65 mmol) at 0° C. The reaction was allowed to stir at room temperature for 5 h. Water (100 mL) was added to the reaction mixture, and the pH was adjusted to 5 with 2N HCl. The aqueous phase was extracted with CH₂Cl₂ (3×150 mL). The combined organic phases were dried over MgSO₄ and concentrated. To the residue was added Et₂O (100 mL). The solid (Compound 14c) was collected by filtration and dried. ¹H NMR (300 MHz, CDCl₃): δ 9.80 (s, 1H), 9.10 (s, 1H), 7.75-8.90 (m, 2H), 7.50 (dd, 1H), 4.50 (q, 2H), 1.50 (t, 3H); MS: m/z 246.1 (M+H)⁺.

B. 4-Chloro-2-pyridin-3-yl-pyrimidine-5-carboxylic acid ethyl ester (14d)

To a suspension of Compound 14c (5.05 g; 20.59 mmol) in DMF (70 mL) was added SOCl₂ (3 mL; 41.23 mmol) dropwise at room temperature. The reaction was stirred at room temperature for 30 min, then poured into an ice water slurry of K₂CO₃ (3.41 g). The resultant solid (Compound 14d) was collected by filtration and dried. ¹H NMR (300 MHz, CDCl₃): δ 9.70 (s, 1H), 9.20 (s, 1H), 7.70-8.85 (m, 2H), 7.50 (dd, 1H), 4.50 (q, 2H), 1.45 (t, 3H); MS: m/z 264.1 (M+H)⁺.

C. 4-(3-Cyano-phenoxy)-2-pyridin-3-yl-pyrimidine-5-carboxylic acid ethyl ester (14e)

A mixture of Compound 14d (1.0 g; 3.79 mmol), 3-cyanophenol (0.587 g; 4.93 mmol) and Cs₂CO₃ (4.93 g; 15.13 mmol) in CH₃CN (25 mL) was stirred at room temperature for 2 h. The suspension was poured into ice-water and extracted with CH₂Cl₂ (3×50 mL). The combined organic phases were dried over MgSO₄ and concentrated to afford Compound 14e. ¹H NMR (300 MHz, CDCl₃): δ 9.40 (s, 1H), 9.25 (s, 1H), 8.70 (d, 1H), 8.45 (m, 1H), 7.45-7.65 (m, 4H), 7.35 (m, 1H), 4.50 (q, 2H), 1.45 (t, 3H); MS: m/z 347.2 (M+H)⁺.

D. 4-(3-Cyano-phenoxy)-2-pyridin-3-yl-pyrimidine-5-carboxylic acid (14f)

To a suspension of Compound 14e (1.06 g; 3.06 mmol) in EtOH (50 mL) was added 0.5N NaOH (9 mL; 4.5 mmol). The reaction was stirred at room temperature for 2 h. The pH of the reaction mixture was adjusted to 2 with 1N HCl. The resultant white solid was collected by filtration to afford Compound 14f. ¹H NMR (300 MHz, DMSO d₆): δ 9.21 (s, 1H), 9.18 (d, 1H), 8.70 (d, 1H), 8.35 (dd, 1H), 7.95 (s, 1H), 7.85 (dd, 1H), 7.75 (m, 2H), 7.50 (dd, 1H); MS: m/z 319.2 (M+H)⁺.

E. [4-(3-Cyano-phenoxy)-2-pyridin-3-yl-pyrimidin-5-yl]carbamic acid tert-butyl ester (14g)

To a solution of Et₃N (0.058 mL; 0.42 mmol) in ^(t)BuOH (9.35 mL) was added 4 Å molecular sieves (3 g) and the mixture was refluxed for 30 min under a N₂ atmosphere. Compound 14f (0.1 g; 0.31 mmol) and diphenylphosphorylazide (0.085 mL; 0.39 mmol) were added to the mixture and refluxed for 3 h under a N₂ atmosphere. The reaction mixture was allowed to cool to room temperature, filtered and concentrated. The resulting residue was suspended in EtOAc (10 mL) and washed with water (10 mL) and brine (10 mL), dried over MgSO₄ and concentrated. The crude product was purified by reverse phase HPLC to give Compound 14g. ¹H NMR (300 MHz, CD₃OD): δ 9.30 (s, 1H), 9.20 (s, 1H), 8.80 (d, 1H), 8.65 (d, 1H), 7.80 (dd, 1H), 7.70 (s, 1H), 7.65 (m, 3H), 1.50 (s, 9H); MS: m/z 390.3 (M+H)⁺.

F. 3-(5-Amino-2-pyridin-3-yl-pyrimidin-4-yloxy)-benzonitrile (15h)

To a solution of Compound 14g (0.78 g; 2.0 mmol) in CH₂Cl₂ (20 mL) was added TFA (4 mL). The mixture was stirred at room temperature for 4 h. The solvent was evaporated under reduced pressure to afford Compound 14h. The crude product was used in the next reaction without further purification. MS: m/z 290.3 (M+H)⁺.

G. 2-(S)-{[4-(3-Cyano-phenoxy)-2-pyridin-3-yl-pyrimidin-5-ylamino]-methyl}-pyrrolidine-1-carboxylic acid tert-butyl ester (14i)

To a suspension of Compound 14h (0.52 g; 1.8 mmol) and Compound 1d (0.505 mL; 2.69 mmol) in 1,2-dichloroethane (10 mL) was added acetic acid (0.103 mL; 1.8 mmol). The reaction was stirred at room temperature for 30 min. Sodium triacetoxyborohydride (0.46 g; 2.17 mmol) was added to the mixture. The mixture was stirred at room temperature for 20 h. Additional sodium triacetoxyborohydride (0.92 g; 4.34 mmol) was added to the mixture. The reaction was stirred at room temperature for 6 h, diluted with EtOAc (50 mL), and washed with H₂O (2×20 mL). The organic layer was dried over MgSO₄ and concentrated. The crude product was purified by reverse phase HPLC to give Compound 14i. ¹H NMR (300 MHz, MeOH-d₄): δ 9.20 (s, 1H), 8.95 (d, 1H), 8.20 (d, 1H), 8.45 (s, 1H), 8.00 (dd, 1H), 7.65-7.8 (m, 4H), 4.20 (m, 1H), 3.3-3.6 (m, 4H), 1.9-2.1 (m, 4H), 1.5 (s, 9H); MS: m/z 473.4 (M+H)⁺.

H. Cpd 135: 3-{2-Pyridin-3-yl-5-[(pyrrolidin-2-(S)-ylmethyl)-amino]-pyrimidin-4-yloxy}-benzonitrile

To a solution of Compound 14i (0.05 g; 0.106 mmol) in CH₂Cl₂ (2 mL) was added TFA (0.4 mL). The mixture was stirred at room temperature for 4 h. The solvent was evaporated under reduced pressure. The crude product was purified by reverse phase HPLC to give Compound 135 as a TFA salt. ¹H NMR (300 MHz, MeOH-d₄): δ 9.20 (s, 1H), 8.95 (d, 1H), 8.75 (d, 1H), 8.35 (s, 1H), 8.00 (dd, 1H), 7.60-7.80 (m, 4H), 4.00 (m, 1H), 3.70 (m, 2H), 3.40 (m, 2H), 2.4 (m, 1H), 2.15 (m, 2H), 1.9 (m, 1H); MS: m/z 373.2 (M+H)⁺.

Following the procedure described above for Example 14 and substituting the appropriate reagents, starting materials and purification methods known to those skilled in the art, the following compounds of the present invention were prepared:

Cpd MS (M + H)⁺ Cpd MS (M + H)⁺ 136 373.3 137 391.3

Example 15

A. N,N-Diethyl-3-methoxy-benzamide (15a)

To a solution of m-anisic acid (0.5 g; 3.29 mmol) and HATU (1.4 g; 3.68 mmol) in DMF (5 mL) was added N,N-diisopropylethylamine (2 mL; 11.48 mmol). The reaction was stirred at room temperature for 30 min. Diethylamine (0.377 mL; 3.62 mmol) was added to the reaction. The mixture was stirred at room temperature for 1.5 d, diluted with H₂O (5 mL), and extracted with EtOAc (2×5 mL). The organic layer was dried over MgSO₄ and concentrated to afford Compound 15a. The crude product was used in the next reaction without further purification. MS: m/z 208.2 (M+H)⁺.

B. N,N-Diethyl-3-hydroxy-benzamide (15b)

To a solution of Compound 15a (0.68 g; 3.28 mmol) in CH₂Cl₂ (50 mL) was added BBr₃ (1.0M in CH₂Cl₂) (16 mL; 16 mmol) dropwise at 0° C. The reaction was stirred at room temperature for 1 h. The mixture was quenched with saturated aqueous NaHCO₃. The organic layer was dried over MgSO₄ and concentrated to afford Compound 15b. The crude product was used in the next reaction without further purification. MS m/z 194.2 (M+H)⁺.

Following the procedure described above for Example 15 and substituting pyrrolidine for diethylamine in Procedure A, the Compound 15c was prepared:

Following the procedure described above for Example 14, substituting Compound 15c for Compound 14c RIGHT?; and substituting the appropriate reagents and purification methods known to those skilled in the art, the following compounds of the present invention were prepared:

Cpd MS (M + H)⁺ Cpd MS (M + H)⁺ 157 447.3 158 445.4

Example 16

A. 4-(2-Chloro-5-nitro-pyrimidin-4-yloxy)-benzoic acid ethyl ester (16a)

To a suspension of Compound 1a (2.0 g; 10.31 mmol) and 0.5N NaHCO₃ (20 mL; 10 mmol) in acetone (60 mL) was added a solution of 4-hydroxy-benzoic acid ethyl ester (1.71 g; 10.29 mmol) in acetone (20 mL) dropwise at 0° C. The mixture was stirred at 0° C. for 1 h. The reaction mixture was concentrated under reduced pressure. The resultant residue was extracted with EtOAc (2×20 mL). The organic layer was washed with brine and dried over MgSO₄ and concentrated. The crude product was purified by normal phase chromatography (SiO₂) to give Compound 16a. ¹H NMR (300 MHz, CDCl₃): δ 9.20 (s, 1H), 8.20 (d, 2H), 7.25 (d, 2H), 4.45 (q, 2H), 1.4 (t, 3H); MS: m/z 324.1 (M+H)⁺.

B. 4-(5-Amino-2-chloro-pyrimidin-4-yloxy)-benzoic acid ethyl ester (16b)

To a solution of Compound 16a (2.12 g; 6.55 mmol) in AcOH (15 mL) and CH₃OH (20 mL) was added Zn (2.57 g; 39.31 mmol) in portions at room temperature. The reaction mixture was stirred at room temperature for 6 h. The solid was collected by filtration and washed with CH₃OH. The filtrate was concentrated. The residue was quenched with aqueous NaOH (<1N) and adjusted to pH ˜7, and extracted with EtOAc (2×20 mL). The organic layer was dried over MgSO₄ and concentrated. The crude product was purified by normal phase chromatography (SiO₂) to give Compound 16b. ¹H NMR (300 MHz, CDCl₃): δ 8.15 (d, 2H), 7.95 (s, 1H), 7.25 (d, 2H), 4.45 (q, 2H), 1.4 (t, 3H); MS: m/z 294.1 (M+H)⁺.

C. 2-(S)-{[2-Chloro-4-(4-ethoxycarbonyl-phenoxy)-pyrimidin-5-ylamino]-methyl}-pyrrolidine-1-carboxylic acid tert-butyl ester (16c) and 4-(2-Chloro-5-ethylamino-pyrimidin-4-yloxy)-benzoic acid ethyl ester (16d)

To a suspension of Compound 16b (0.82 g; 2.79 mmol) and Boc-L-prolinal (Compound 1d) (0.67 g; 3.36 mmol) in 1,2-dichloroethane (10 mL) was added acetic acid (0.16 mL, 2.79 mmol). The reaction was stirred at room temperature for 30 min. Sodium triacetoxyborohydride (0.89 g; 4.20 mmol) was added to the mixture. The mixture was stirred at room temperature for 20 h. Additional sodium triacetoxyborohydride (0.89 g; 4.20 mmol) was added to the mixture. The reaction was stirred at room temperature for 2 d, diluted with EtOAc (50 mL), and washed with H₂O (2×20 mL). The organic layer was dried over MgSO₄ and concentrated. The crude product was purified by normal phase chromatography (SiO₂) to give Compound 16c and Compound 16d. Compound 16c-MS: m/z 477.3 (M+H)⁺. Compound 16d-MS: m/z 322.2 (M+H)⁺.

D. 2-(S)-{[4-(4-Ethoxycarbonyl-phenoxy)-2-pyridin-3-yl-pyrimidin-5-ylamino]-methyl}-pyrrolidine-1-carboxylic acid tert-butyl ester (16e)

To a suspension of Compound 16c (0.76 g; 1.59 mmol), pyridin-3-yl boronic acid (0.235 g; 1.91 mmol) and Cs₂CO₃ (1.30 g; 3.99 mmol) in a dioxane (10 mL)/EtOH (2 mL) mixture, was added 1,1′-bis(diphenylphosphino)ferrocene palladium (II) chloride complex with dichloromethane (0.116 g; 0.159 mmol). The mixture was stirred at 80° C. for 4 h, and then cooled to room temperature. The solid was collected by filtration and washed with CH₃OH. The filtrate was concentrated. The crude product was purified by reverse phase HPLC to give Compound 16e. MS: m/z 520.3 (M+H)⁺.

E. 2-(S)-{[4-(4-Carboxy-phenoxy)-2-pyridin-3-yl-pyrimidin-5-ylamino]-methyl}-pyrrolidine-1-carboxylic acid tert-butyl ester (16f)

To a suspension of Compound 16e (0.4 g; 0.77 mmol) in EtOH (10 mL) was added 0.5N NaOH (2.3 mL; 1.15 mmol). The reaction was stirred at room temperature for 3 h. Additional 0.5N NaOH (6 mL; 3 mmol) was added to the mixture. The reaction was stirred at room temperature for 3 h. The solution was adjusted to pH 2 with 1N HCl. The white solid was collected by filtration to afford Compound 16f. MS: m/z 492.3 (M+H)⁺.

F. 2-(S)-({4-[4-(Piperidine-1-carbonyl)-phenoxy]-2-pyridin-3-yl-pyrimidin-5-ylamino}-methyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (16 g)

To a solution of Compound 16f (0.08 g; 0.16 mmol) and HATU (0.065 g; 0.17 mmol) in DMF (3 mL) was added N,N-diisopropylethylamine (0.115 mL; 0.66 mmol). The reaction was stirred at room temperature for 30 min. Piperidine (0.017 mL; 0.17 mmol) was added to the reaction. The mixture was stirred at room temperature for 1 h, poured into H₂O (3 mL), and extracted with EtOAc (2×5 mL). The organic layer was dried over MgSO₄ and concentrated to afford Compound 16g. The crude product was used in the next reaction without further purification. MS: m/z 559.3 (M+H)⁺.

G. Cpd 160: Piperidin-1-yl-(4-{2-pyridin-3-yl-5-[(pyrrolidin-2-(S)-ylmethyl)-amino]-pyrimidin-4-yloxy}-phenyl)-methanone

To a solution of Compound 16g (0.089 g; 0.16 mmol) in CH₂Cl₂ (4 mL) was added TFA (0.8 mL). The mixture was stirred at room temperature for 4 h. The solvent was evaporated under reduced pressure. The crude product was purified by reverse phase HPLC to give Compound 160 as a TFA salt. ¹H NMR (300 MHz, MeOH-d₄): δ 9.21 (s, 1H), 8.95 (d, 1H), 8.75 (d, 1H), 8.35 (s, 1H), 7.95 (dd, 1H), 7.55 (d, 2H), 7.40 (d, 2H), 4.05 (m, 1H), 3.6-3.85 (m, 4H), 3.3-3.55 (m, 4H), 2.35 (m, 1H), 2.20 (m, 2H), 1.9 (m, 1H), 1.55-1.85 (m, 6H); MS: m/z 459.3 (M+H)⁺.

Following the procedure described above for Example 16 and substituting the appropriate reagents, starting materials and purification methods known to those skilled in the art, the following compounds of the present invention were prepared:

Cpd MS (M + H)⁺ Cpd MS (M + H)⁺ 161 461.2 162 474.3 166 445.4 167 459.3 168 461.4 169 474.3 170 465.3 171 463.4 172 477.3 173 479.3 174 492.3 175 447.3 176 463.4

Cpd 159

Deprotection of Compound 16f was performed using TFA/CH₂Cl₂ as described in Procedure G of Example 16 to afford Compound 159 as a TFA salt. MS: m/z 392.3 (M+H)⁺.

Cpd 163

The title compound was prepared in an analogous manner to Cpd 159, substituting 3-hydroxy-benzoic acid ethyl ester for 4-hydroxy-benzoic acid ethyl ester in Procedure A of Example 16. MS: m/z 392.3 (M+H)⁺.

Cpd 164

The title compound was prepared in an analogous manner to Cpd 159, substituting 3-hydroxy-benzoic acid ethyl ester for 4-hydroxy-benzoic acid ethyl ester in Procedure A and substituting 5-fluoropyridin-3-yl boronic acid for pyridin-3-yl boronic acid in Procedure D of Example 16. MS: m/z 410.2 (M+H)⁺.

Cpd 165

The title compound was prepared in an analogous manner to Cpd 159, substituting 5-fluoropyridin-3-yl boronic acid for pyridin-3-yl boronic acid in Procedure D of Example 16. MS: m/z 410.2 (M+H)⁺.

Example 17

A. 4-(4-tert-Butoxycarbonylaminophenoxy)-2-pyridin-3-ylpyrimidine-5-carboxylic acid ethyl ester (17a)

Using an adaptation of the method described in Procedure C of Example 14, substituting (4-hydroxyphenyl)carbamic acid t-butyl ester for 3-cyanophenol, the title Compound 17a was obtained. MS: m/z 437.3 (M+H)⁺.

B. 4-(4-tert-Butoxycarbonylaminophenoxy)-2-pyridin-3-ylpyrimidine-5-carboxylic acid (17b)

Using an adaptation of the method described in Procedure D of Example 14, substituting Compound 17a for Compound 14e, the title Compound 17b was obtained. MS: m/z 409.2 (M+H)⁺.

C. 4-(4-Aminophenoxy)-2-pyridin-3-ylpyrimidine-5-carboxylic acid (17c)

To a solution of Compound 17b (1.5 g; 3.6 mmol) in CH₂Cl₂ (30 mL) was adde TFA (10 mL). The solution was stirred at room temperature for 1.5 h, and the solvent was evaporated in vacuo. The residue was triturated with Et₂O, collected the solid and dried to afford the title Compound 17c (2.25 g; 96% yield based on tri-TFA salt). MS: m/z 309.2 (M+H)⁺.

D. 4-[4-(Cyclopropanecarbonylamino)phenoxy]-2-pyridin-3-ylpyrimidine-5-carboxylic acid (17d)

To a solution of Compound 17c (0.5 g; 1.6 mmol) in CH₂Cl₂ (6 mL) was added Et₃N (0.72 mL; 6.4 mmol) and cyclopropylcarbonyl chloride (0.19 mL; 2.1 mmol). The solution was stirred at room temperature for 1 h, then poured the reaction mixture into water. Filtered to collect the solid and dried to afford Compound 17d (410 mg; 68% yield). MS: m/z 376.1 (M+H)⁺.

E. {4-[4-(Cyclopropanecarbonylamino)phenoxy]-2-pyridin-3-ylpyrimidin-5-yl}-carbamic acid tert-butyl ester (17e)

Using an adaptation of the method described in Procedure E of Example 14, substituting Compound 17d for Compound 14f, the title Compound 17e (16% yield) was obtained. MS: m/z 448.2 (M+H)⁺.

F. Cyclopropanecarboxylic acid [4-(5-amino-2-pyridin-3-yl-pyrimidin-4-yloxy)-phenyl]amide (17f)

Using an adaptation of the method described in Procedure F of Example 14, substituting Compound 17e for Compound 14g, the title Compound 17f (78% yield) was obtained. The crude product was used in the next reaction without further purification. MS: m/z 347.3 (M+H)⁺.

G. 2-(S)-({4-[4-(Cyclopropanecarbonyl-amino)-phenoxy]-2-pyridin-3-yl-pyrimidin-5-ylamino}-methyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (17g)

Using an adaptation of the method described in Procedure G of Example 14, substituting Compound 17f for Compound 14h, the title Compound 17g was obtained. MS: m/z 531.3 (M+H)⁺.

H. Cpd 138: Cyclopropanecarboxylic acid (4-{2-pyridin-3-yl-5-[(pyrrolidin-2-(S)-ylmethyl)-amino]-pyrimidin-4-yloxy}-phenyl)-amide

Using an adaptation of the method described in Procedure H of Example 15, substituting Compound 17g for Compound 14i, the title Compound 138 (15% yield based on di-TFA salt) was obtained. ¹H-NMR (300 MHz, DMSO-d₆): δ 8.6 (d, 2H), 8.5 (m, 1H), 8.3 (m, 2H), 7.7 (m, 2H), 7.5 (m, 1H), 7.25 (m, 2H), 6.3 (m, 1H), 3.9 (m, 1H), 3.5 (m, 2H), 3.2 (m, 2H) 3.1-2.8 (m, 2H), 2.15 (m, 1H), 1.9 (m, 2H), 1.8-1.6 (m, 3H), 0.9 (d, 2H); MS: m/z 431.3 (M+H)⁺.

Example 18

A. 2-(S)-{[2-Chloro-4-(4-hydroxymethyl-phenoxy)-pyrimidin-5-ylamino]-methyl}-pyrrolidine-1-carboxylic acid tert-butyl ester (18a)

The title compound was prepared in a same manner to Compound 1e in Example 1. Using an adaptation of the method described in Procedures A-C, substituting 4-hydroxymethyl-phenol for 4-methoxyphenol in Procedure A, the title Compound 18a was obtained. MS: m/z 435.2 (M+H)⁺.

B. 2-(S)-{[4-(4-Hydroxymethyl-phenoxy)-2-pyridin-3-yl-pyrimidin-5-ylamino]-methyl}-pyrrolidine-1-carboxylic acid tert-butyl ester (18b)

Using an adaptation of the method described in Procedure D of Example 1, substituting Compound 18a for Compound 1e and substituting pyridin-3-yl boronic acid for Compound 1f, the title Compound 18b (73% yield) was obtained. MS: m/z 478.2 (M+H)⁺.

C. 2-(S)-{[4-(4-Fluoromethyl-phenoxy)-2-pyridin-3-yl-pyrimidin-5-ylamino]-methyl}-pyrrolidine-1-carboxylic acid tert-butyl ester (18c)

To a solution of (diethylamino)sulfur trifluoride (0.036 mL; 0.28 mmol) in CH₂Cl₂ (2 mL), cooled to ˜78° C., was added a solution of Compound 18b (100 mg; 0.21 mmol) in CH₂Cl₂ (1 mL). The reaction mixture was stirred at ˜78° C. for 20 min. The resultant mixture was partitioned between EtOAc and H₂O. The organic phase was washed with water and dried over Na₂SO₄. The mixture was filtered and the solvent removed under reduced pressure to give the crude material. The crude material was purified by flash column chromatography (SiO₂), eluting with a heptane-EtOAc gradient to afford Compound 18c (50 mg; 50% yield). MS: m/z 480.2 (M+H)⁺.

D. Cpd 217: [4-(4-Fluoromethyl-phenoxy)-2-pyridin-3-yl-pyrimidin-5-yl]-pyrrolidin-2-(S)-ylmethyl-amine

Using an adaptation of the method described in Procedure E of Example 1, substituting Compound 18c for Compound 1g, the title Compound 217 was obtained as a HCl salt. ¹H-NMR (400 MHz, MeOH-d₄): δ 9.21 (br. s, 1H), 8.73-8.74 (m, 1H), 8.63 (br. s, 1H), 8.27-8.29 (m, 1H), 7.75 (br. s, 1H), 7.45-7.58 (m, 2H), 7.30-7.39 (m, 2H), 5.36-5.51 (m, 2H), 4.02-4.05 (m, 1H), 3.67-3.73 (m, 2H), 3.41-3.48 (m, 2H), 2.32-2.38 (m, 1H), 2.09-2.21 (m, 2H), 1.86-1.95 (m, 1H); MS: m/z 380.2 (M+H)⁺.

Following the procedure described above for Example 18 and substituting the appropriate reagents, starting materials and purification methods known to those skilled in the art, the following compound of the present invention was prepared:

Cpd MS (M + H)⁺ 348 405.2

Example 19

A. 2-(S)-{[2-Chloro-4-(4-fluoromethyl-phenoxy)-pyrimidin-5-ylamino]-methyl}-pyrrolidine-1-carboxylic acid tert-butyl ester (19a)

Using an adaptation of the method described in Procedure C of Example 18, substituting Compound 18a for Compound 18b, the title Compound 19a (23% yield) was obtained. MS: m/z 437.2 (M+H)⁺.

B. 2-(S)-{[2-Pyridin-3-yl-4-(4-pyridin-3-ylmethyl-phenoxy)-pyrimidin-5-ylamino]-methyl}-pyrrolidine-1-carboxylic acid tert-butyl ester (19b)

Using an adaptation of the method described in Procedure D of Example 1, substituting Compound 19a for Compound 1e and substituting pyridin-3-yl boronic acid for Compound 1f, the title Compound 19b (22% yield) was obtained. ¹H-NMR (400 MHz, CDCl₃): δ 9.26 (s, 1H), 8.55 (d, 1H), 8.51 (dd, 2H), 8.32 (d, 1H), 8.01-8.06 (m, 1H), 7.53 (d, 1H), 7.18-7.27 (m, 6H), 5.78 (br. s, 0.7H), 4.85 (br. s, 0.3; H), 4.21-4.32 (m, 1H), 4.04 (s, 2H), 3.21-3.54 (m, 4H), 1.84-2.14 (m, 4H); MS: m/z 539.3 (M+H)⁺.

C. Cpd 209: [2-Pyridin-3-yl-4-(4-pyridin-3-ylmethyl-phenoxy)-pyrimidin-5-yl]-pyrrolidin-2-(S)-ylmethyl-amine

Using an adaptation of the method described in Procedure E of Example 1, substituting Compound 19b for Compound 1g, the title Compound 209 was obtained as a HCl salt. ¹H-NMR (400 MHz, MeOH-d₄): δ 9.12 (br. s, 1H), 8.44-8.57 (m, 4H), 8.23 (s, 1H), 7.94 (d, 1H), 7.47-7.57 (m, 2H), 7.41 (d, 2H), 7.29 (d, 2H), 4.17 (s, 2H), 4.01-4.04 (m, 1H), 3.67-3.70 (m, 2H), 3.45-3.54 (m, 2H), 2.31-2.39 (m, 1H), 2.08-2.21 (m, 2H), 1.85-1.95 (m, 1H); MS: m/z 439.2 (M+H)⁺.

Example 20

A. 2,4,5-Tribromo-pyrimidine (20b)

To a pressure vessel, a suspension of 2,4-dichloro-5-bromo-pyrimidine (Compound 20a) (3.0 g; 13.2 mmol) in HBr solution (33 wt % in AcOH) (35 mL) was heated at 50° C. for 4 h before cooling in an ice bath. The reaction mixture was poured into ice/water (2-fold volume) and was extracted with EtOAc. The organic phase was washed sequentially with H₂O and brine, and dried over Na₂SO₄. The mixture was filtered and the solvent evaporated under reduced pressure to give the crude material. The crude material was recrystallized from EtOAc-hexanes to afford Compound 20b (3.75 g; 90% yield) as a yellow solid. ¹H-NMR (400 MHz, CDCl₃): δ 8.58 (s, 1H); MS: m/z 314.8 (M+H)⁺.

B. 2,5-Dibromo-4-(4-methoxy-phenoxy)-pyrimidine (26c)

A mixture of Compound 20b (0.39 g; 1.23 mmol), K₂CO₃ (0.25 g, 1.85 mmol) and 4-methoxy-phenol (0.15 g; 1.23 mmol) in dioxane (4 mL) was heated at 65° C. for 20 h. The reaction mixture was filtered and the filtrate was diluted with EtOAc and H₂O. The organic phase was washed sequentially with H₂O and brine, and dried over Na₂SO₄. The mixture was filtered and the solvent evaporated under reduced pressure to give the crude material. Recrystallized the crude material from EtOAc-hexane to afford Compound 20c (0.42 g; 95% yield) as white solid. ¹H-NMR (400 MHz, CDCl₃): δ 8.49 (s, 1H), 7.10 (d, 2H), 6.95 (d, 2H), 3.84 (s, 3H); MS: m/z 359.0 (M+H)⁺.

C. 5-Bromo-4-(4-methoxy-phenoxy)-2-pyridin-3-yl-pyrimidine (20d)

Under argon pressure, a mixture of Compound 20c (2.27 g; 6.31 mmol), pyridine-3-boronic acid (853 mg; 6.94 mmol), Na₂CO₃ (1.34 g; 12.6 mmol) and [1,1′-Bis(diphenylphosphino)-ferrocene]dichloro-palladium(II) (258 mg, 0.32 mmol) in dioxane (32 mL) was stirred at room temperature for 5 min, and then D.I. water (8 mL) was added. The whole mixture was heated at 55° C. under argon pressure for 20 h. Diluted the resulted mixture with EtOAc, washed with saturated NH₄Cl_((aq)) and H₂O. The organic phase was washed sequentially with H₂O, and then dried over Na₂SO₄. The mixture was filtered and the filtrate was evaporated under reduced pressure to give the crude material. The crude material was purified by flash column chromatography (SiO₂), eluting with a heptane-EtOAc gradient to afford Compound 20d (1.44 g; 64% yield) as off-white solid. ¹H-NMR (400 MHz, CDCl₃): δ 9.33 (dd, 1H), 8.77 (s, 1H), 8.64 (dd, 1H), 8.41 (dt, 1H), 7.32 (td, 1H), 7.16 (dd, 2H), 6.97 (dd, 2H), 3.87 (s, 3H); MS: m/z 358.0 (M+H)⁺.

D. 4-[4-(4-Methoxy-phenoxy)-2-pyridin-3-yl-pyrimidin-5-yl]-piperazine-1-carboxylic acid tert-butyl ester (20e)

To a dry Schlenk tube was added a mixture of Compound 20d (100 mg; 0.28 mmol), piperazine-1-carboxylic acid tert-butyl ester (52 mg; 0.56 mmol), Cs₂CO₃ (227 mg; 0.70 mmol), (Diphenylphosphino)ferrocene (54 mg; 0.10 mmol), and Tris(dibenzylideneacetone)dipalladium(0) (25.6 mg; 0.028 mmol). Sealed the tube with a teflon-lined septum, evacuated, and refilled with argon. Added dioxane (0.3 mL; reaction conc. >0.75M) to the mixture via syringe. The mixture was heated at 95° C. for 3 h. Diluted the resulted mixture with EtOAc, washed with saturated NH₄Cl_((aq)) and H₂O. The organic phase was washed sequentially with H₂O, and then dried over Na₂SO₄. The mixture was filtered and the filtrate was evaporated under reduced pressure to give the crude material. The crude material was purified by flash column chromatography (SiO₂), eluting with a heptane-EtOAc gradient to afford Compound 20e (104 mg; 80% yield). ¹H-NMR (400 MHz, CDCl₃): δ 9.28 (d, 1H), 8.58 (dd, 1H), 8.35 (dt, 1H), 8.22 (s, 1H), 7.29 (td, 1H), 7.14 (dd, 2H), 6.98 (dd, 2H), 3.87 (s, 3H), 3.66 (t, 4H), 3.25 (t, 4H), 1.56 (s, 9H); MS: m/z 464.2 (M+H)⁺.

E. Cpd 327: 4-(4-Methoxy-phenoxy)-5-piperazin-1-yl-2-pyridin-3-yl-pyrimidine

Using an adaptation of the method described in Procedure E of Example 1, substituting Compound 20e for Compound 1g, the title Compound 327 was obtained as a HCl salt. Free base-¹H-NMR (400 MHz, CDCl₃): δ 9.28 (d, 1H), 8.57 (dd, 1H), 8.34 (dt, 1H), 8.23 (s, 1H), 7.28 (td, 1H), 7.15 (dd, 2H), 6.97 (dd, 2H), 3.87 (s, 3H), 3.28 (t, 4H), 3.11 (t, 4H); MS: m/z 364.2 (M+H)⁺.

Following the procedure described above for Example 20 and substituting the appropriate reagents, starting materials and purification methods known to those skilled in the art, the following compounds of the present invention were prepared:

Cpd MS (M + H)⁺ Cpd MS (M + H)⁺ 324 363.2 325 389.2 326 389.2 199 403.2 328 389.2 329 403.2 207 403.2 208 403.2 329 403.2 331 389.2 215 389.2 332 403.2 333 403.2 334 403.2 336 378.0 224 364.0 225 392.0 226 350.0 305 392.0 236 378.0 338 401.0 237 364.0 339 364.0 341 410.0 340 350.0 342 394.0 245 408.0 344 403.0 343 403.0 246 408.0 345 403.0 252 424.2 346 408.0 347 424.0 254 424.0 255 410.0 348 410.0 256 394.0 349 394.0 257 378.0 258 392.2 259 392.0 350 438.0 351 378.0 352 378.0 261 378.0 354 378.0 355 392.2 356 378.0 358 392.2 296 352.0 267 392.2

Following the procedure described above for Example 20 and substituting the appropriate reagents, starting materials and purification methods known to those skilled in the art, the following compounds of the present invention were prepared as mixtures (contained 4 isomers).

Cpd MS (M + H)⁺ Cpd MS (M + H)⁺ 306 392.0 312 438.0 309 422.2 315 406.2

Using purification methods known to those skilled in the art, the above mixtures of the present invention were further separated into their corresponding diastereoisomers and/or single stereoisomer.

MS Cpd stationary phase/order of elution off the column (M + H)⁺ 307 C-18 (CH₃CN—H₂O)/first peak off column 392.0 308 C-18 (CH₃CN—H₂O)/first peak off column 392.0 311 CHIRALPAK ® AD ™ (50% methanol with 0.5% 422.0 isopropylamine/50% Ethanol with 0.5% isopropylamine; flow rate: 1.0 mL/min)/first peak off column 312 CHIRALPAK ® AD ™ (50% methanol with 0.5% 422.0 isopropylamine/50% Ethanol with 0.5% isopropylamine; flow rate: 1.0 mL/min)/second peak off column 313 CHIRALPAK ® AD ™ (50% methanol with 0.5% 422.0 isopropylamine/50% Ethanol with 0.5% isopropylamine; flow rate: 1.0 mL/min)/third peak off column 314 CHIRALPAK ® AD ™ (50% methanol with 0.5% 422.0 isopropylamine/50% Ethanol with 0.5% isopropylamine; flow rate: 1.0 mL/min)/fourth peak off column 316 CHIRALCEL ® OJ ™ (85% heptane/7.5% ethanol/ 438.2 7.5% ammonia sat. in methanol 7N, flow rate: 2.0 mL/min)/third peak off column 317 CHIRALCEL ® OJ ™ (85% heptane/7.5% ethanol/ 438.2 7.5% ammonia sat. in methanol 7N, flow rate: 2.0 mL/min)/fourth peak off column 318 CHIRALCEL ® OJ ™ (85% heptane/7.5% ethanol/ 438.2 7.5% ammonia sat. in methanol 7N, flow rate: 2.0 mL/min)/first peak off column 319 CHIRALCEL ® OJ ™ (85% heptane/7.5% ethanol/ 438.2 7.5% ammonia sat. in methanol 7N, flow rate: 2.0 mL/min)/second peak off column 321 CHIRALPAK ® AD ™ (20% IPA in hexane at 15 392.2 mL/min)/third peak off column 322 CHIRALPAK ® AD ™ (20% IPA in hexane at 15 392.2 mL/min)/fourth peak off column 323 CHIRALPAK ® AD ™ (20% IPA in hexane at 15 392.2 mL/min)/first peak off column ²Using Boc-protected mixtures, chiral separations were performed to obtain the Boc-protected single isomers, which were then deprotected to give the example compounds.

Example 21 An Alternative Route for Preparing Compounds Described in Example 20

A. 2,5-Dichloro-4-(4-methoxy-phenoxy)-pyrimidine (21b)

To a solution of Compound 21a (5 g; 27.26 mmol) in acetone (480 mL), cooled to 0° C., was added a solution of 4-methoxy-phenol (3.38 g; 27.26 mmol) in a mixture of 1 N NaHCO₃ (aq) (27.3 mL) and H₂O (120 mL), dropwise, by an additional funnel. Upon completion of the addition, the reaction mixture was allowed to warm to ambient temperature, and then stirred at room temperature for 3 h. The resultant mixture was concentrated in vacuo, and the resultant residue was diluted with EtOAc, then washed sequentially with 1 N NaOH (aq) and H₂O. The organic phase was washed sequentially with H₂O and brine, and dried over Na₂SO₄. The mixture was filtered and the filtrate concentrated under reduced pressure to give a crude material. The crude material was recrystallized from EtOAc-hexanes to afford Compound 21b (7.0 g; 94% yield). ¹H-NMR (400 MHz, CDCl₃): δ 8.46 (s, 1H), 7.09-7.27 (m, 2H), 6.94-6.98 (m, 2H), 3.85 (s, 3H); MS: m/z 271.0 (M+H)⁺.

B. 5-Chloro-4-(4-methoxy-phenoxy)-2-pyridin-3-yl-pyrimidine (21c)

Under argon pressure, a mixture of Compound 21b (2.43 g; 8.98 mmol), pyridin-3-yl boronic acid (1.43 g; 11.67 mmol), Na₂CO₃ (1.90 g; 17.96 mmol) and [1,1′-bis(diphenylphosphino)-ferrocene]dichloro-palladium(II) (370 mg, 0.45 mmol) in dioxane (35 mL) was stirred at room temperature for 5 min, and then deionized water (7 mL) was added. The mixture was heated at 75° C. under an argon atmosphere for 20 h. The resultant mixture was diluted with EtOAc, washed with saturated NH₄Cl (aq) and H₂O. The organic phase was washed sequentially with H₂O, and then dried over Na₂SO₄. The mixture was filtered and the filtrate was evaporated under reduced pressure to give the crude material. The crude material was purified by flash column chromatography (SiO₂), eluting with a heptane-EtOAc gradient to afford Compound 23c (2.10 g; 75% yield). ¹H-NMR (400 MHz, CDCl₃): δ 9.34 (dd, 1H), 8.6 (s, 1H), 8.65 (dd, 1H), 8.42 (dt, 1H), 7.31-7.34 (m, 1H), 7.15-7.19 (m, 2H), 6.97-7.01 (m, 2H), 3.88 (s, 3H); MS: m/z 314.0 (M+H)⁺.

C. 4-[4-(4-Methoxy-phenoxy)-2-pyridin-3-yl-pyrimidin-5-yl]-2-(R)-methyl-piperazine-1-carboxylic acid tert-butyl ester (21d)

Using an adaptation of the method described in Procedure D of Example 22, substituting 2-(R)-methyl-piperazine-1-carboxylic acid tert-butyl ester for piperazine-1-carboxylic acid tert-butyl ester, the title Compound 23d was obtained. ¹H-NMR (400 MHz, CDCl₃): δ 9.30 (br. s, 1H), 8.58 (br. s, 1H), 8.36 (d, 1H), 8.20 (s, 1H), 7.25-7.32 (m, 1H), 7.13-7.18 (m, 2H), 6.96-7.00 (m, 2H), 4.40 (br. s, 1H), 4.02-4.05 (m, 1H), 3.88 (s, 3H), 3.59-3.62 (m, 1H), 3.30-3.51 (m, 1H), 2.89-2.96 (m, 2H), 1.50 (s, 9H), 1.40 (d, 3H); MS: m/z 478.0 (M+H)⁺.

D. Cpd 357: 4-(4-Methoxy-phenoxy)-5-[3-(R)-methyl-piperazin-1-yl]-2-pyridin-3-yl-pyrimidine

Using an adaptation of the method described in Procedure E of Example 1, substituting Compound 21d for Compound 1g, the title Compound 357 was obtained as a HCl salt. Free base-¹H-NMR (400 MHz, CDCl₃): δ 9.29 (d, 1H), 8.58 (dd, 1H), 8.36 (dt, 1H), 8.23 (s, 1H), 7.25-7.30 (m, 1H), 7.14-7.18 (m, 2H), 6.96-7.00 (m, 2H), 3.88 (s, 3H), 3.60-3.67 (m, 2H), 3.12-3.18 (m, 3H), 2.85-2.92 (m, 1H), 2.53-2.58 (m, 1H), 1.18 (d, 3H); MS: m/z 378.0 (M+H)⁺.

Following the procedure described above for Example 21 and substituting the appropriate reagents, starting materials and purification methods known to those skilled in the art, the following compounds of the present invention were prepared:

Cpd MS (M + H)⁺ Cpd MS (M + H)⁺ 320 374.2 360 422.2 361 422.0

Cpd 320

The title compound was prepared in an analogous manner to Compound 21e of Example 21, substituting 4-cyclopropyl-phenol⁴ for 4-methoxy-phenol in Procedure A, and substituting piperazine-1-carboxylic acid tert-butyl ester for 2-(R)-methyl-piperazine-1-carboxylic acid tert-butyl ester in Procedure C. ¹H-NMR (400 MHz, MeOH-d₄): δ 9.11 (d, 1H), 8.49 (dd, 1H), 8.40 (dt, 1H), 8.29 (s, 1H), 7.42 (dd, 1H), 7.15-7.20 (m, 2H), 7.10-7.12 (m, 2H), 3.29-3.32 (m, 4H), 3.04-3.06 (m, 4H), 1.94-2.01 (m, 1H), 0.98-1.03 (m, 2H), 0.70-0.74 (m, 2H); MS: m/z 374.2 (M+H)⁺. ⁴4-Cyclopropyl-phenol was prepared by the following synthetic scheme and procedure:

A. 4-Cyclopropyl-phenol

To a solution of diethylzinc (59 mL, 65.9 mmol) in toluene (80 mL) was added acetic acid 4-vinyl-phenyl ester (5 mL, 32.7 mmol) and diiodomethane (6.86 mL, 85 mmol). The resultant mixture was stirred at room temperature for 5 h, and then heated to reflux for 12 h. The reaction mixture was quenched with 2N HCl solution, the organic layer separated, washed with brine, dried over Na₂SO₄, and concentrated to afford a brown oil (4.5 g). The brown oil (4.5 g) was dissolved in MeOH/THF (20/20 mL), then treated with Na₂CO₃ (5.41 g, 51.1 mmol) at room temperature for 2 h. The reaction mixture was diluted with EtOAc, washed sequentially with saturated NH₄Cl (aq) and H₂O, and extracted with EtOAc (3×). The organic extracts were combined, dried over Na₂SO₄ and concentrated under reduced pressure to afford the title compound (3.2 g; 94% yield), which was used directly without further purification.

Example 22

A. (3-Benzyloxycarbonylamino-cyclohexyl)-carbamic acid tert-butyl ester (22b, 22c)

To a mixture of (3-amino-cyclohexyl)-carbamic acid tert-butyl ester (22a) (1.5 g, 7 mmol) and benzyloxycarbonyl chloride (1.1 mL; 7.7 mmol) in CH₂Cl₂ (30 mL) at −20° C. was added diisopropylmethylamine (2.4 mL; 14 mmol) dropwise under argon atmosphere. The reaction mixture was stirred for 15 min at the same temperature, and it was allowed to warm to room temperature and stirred for an additional 2 h. The reaction mixture was diluted with CH₂Cl₂ and washed with brine. The organic phase was dried and concentrated to give a crude material. The crude material was purified by flash column chromatography (SiO₂), eluting with a heptane-EtOAc gradient to afford Compound 22b (second fraction; 1,3-cis racemic mixture) (1.8 g; 74% yield) and Compound 22c (first fraction; 1,3-trans racemic mixture). Compound 22b: ¹H-NMR (400 MHz, CDCl₃): δ 7.30-7.40 (m, 5H), 5.09 (s, 2H), 4.59 (br. s, 1H), 4.37 (br. s, 1H), 3.54 (br. s, 2H), 2.29-2.31 (m, 1H), 1.99 (br. s, 2H), 1.76-1.81 (m, 1H), 1.44 (s, 9H), 1.34-1.44 (m, 1H), 0.90-1.05 (m, 3H); MS: m/z 249.0 (M+H-Boc)⁺. Compound 22c: ¹H-NMR (400 MHz, CDCl₃): δ 7.30-7.40 (m, 5H), 5.09 (s, 2H), 4.78 (br. s, 1H), 4.56 (br. s, 1H), 3.77-3.85 (m, 2H), 1.68-1.79 (m, 4H), 1.53-1.62 (m, 2H), 1.38-1.49 (m, 2H), 1.45 (s, 9H); MS: m/z 249.0 (M+H-Boc)⁺.

B. [3-(S)-Benzyloxycarbonylamino-cyclohexyl]-1-(R)-carbamic acid tert-butyl ester (27d) and [3-(R)-Benzyloxycarbonylamino-cyclohexyl]-1-(S)-carbamic acid tert-butyl ester (22e)

Compound 22b (850 mg) was separated into two enantiomeric pure compounds, Compound 22d (340 mg; the first fraction) and Compound 22e (365 mg; the second fraction), by using CHIRALPAK® AD™ column (mobile phase: 9% isopropanol in hexanes; flow rate: 60 mL/min). Compound 22d: ¹H-NMR (400 MHz, CDCl₃): δ 7.30-7.39 (m, 5H), 5.09 (s, 2H), 4.60 (br. s, 1H), 4.38 (br. s, 1H), 3.54 (br. s, 2H), 2.28-2.31 (m, 1H), 1.99 (br. s, 2H), 1.75-1.81 (m, 1H), 1.44 (s, 9H), 1.34-1.44 (m, 1H), 0.89-1.05 (m, 3H); MS: m/z 249.0 (M+H-Boc)⁺. Compound 22e: ¹H-NMR (400 MHz, CDCl₃): δ 7.30-7.39 (m, 5H), 5.09 (s, 2H), 4.60 (br. s, 1H), 4.39 (br. s, 1H), 3.54 (br. s, 2H), 2.28-2.32 (m, 1H), 1.99 (br. s, 2H), 1.75-1.81 (m, 1H), 1.44 (s, 9H), 1.34-1.44 (m, 1H), 0.91-1.05 (m, 3H); MS: m/z 249.0 (M+H-Boc)⁺; [α]_(D)=−9.0 (c=1.2 in CHCl₃). The absolute stereochemistry of Compound 22e was determined by comparing the optical rotation of the synthetic (3R-Amino-cyclohexyl)-1S-carbamic acid tert-butyl ester³ with the material from chiral HPLC seperation. ³An alternative approach of synthesizing enantiomeric pure [3-(R)-Amino-cyclohexyl]-1-(S)-carbamic acid tert-butyl ester was described in the following scheme and procedure:

B1. [3-(R)-Amino-cyclohexyl]-1-(S)-carbamic acid tert-butyl ester (22k)

To a solution of Compound 22j (prepared according to the literature procedure described in Bioorganic & Medicinal Chemistry 2005, 13, 2509) (294 mg, 1.21 mmol) and Et₃N (0.185 mL, 1.33 mmol) in toluene (7 mL) was added (PhO)₂P(O)N₃ (0.29 mL, 1.34 mmol). The reaction mixture was heated to reflux for 1 h before BnOH (0.5 mL, 4.8 mmol) was added. The reaction was heated to reflux for another 7 h. The mixture was concentrated and purified by flash column chromatography (SiO₂, 30% EtOAc/heptane) to give Compound 22k (0.1 g; 24% yield). ¹H-NMR (400 MHz, CDCl₃): δ 7.35 (m, 5H), 5.08 (s, 2H), 4.67 (d, 1H), 4.42 (s, 1H), 3.53 (m, 2H), 2.29 (d, 1H), 1.97 (s, 2H), 1.75 (m, 1H), 1.43 (s, 9H), 1.39 (m, 1H), 0.98 (m, 3H); MS: m/z 371 (M+Na)⁺; [α]_(D)=−6.3 (c=1.1 in CHCl₃).

C. [3-(S)-Amino-cyclohexyl]-1-(R)-carbamic acid tert-butyl ester (22f)

A portion of 10% Pd/C (42 mg), Compound 22d (214 mg; 0.61 mmol) and MeOH (35 mL) was added to a Parr bottle. The reaction mixture was shaken under a 40-psi H₂ atmosphere for 2 h. The resultant mixture was passed through a bed of diatomaceous earth and the filtrate was evaporated in vacuo to afford Compound 22f (90 mg) as a white solid. The compound was used in the next reaction without further purification. ¹H-NMR (400 MHz, CDCl₃): δ 4.55-4.66 (m, 1H), 3.48-3.50 (m, 1H), 2.75-2.81 (m, 1H), 2.08-2.14 (m, 1H), 1.91-1.94 (m, 1H), 1.74-1.82 (m, 2H), 1.45 (s, 9H), 1.26-1.45 (m, 1H), 0.89-1.05 (m, 3H); MS: m/z 215.2 (M+H)⁺.

D. 5-Chloro-4-(4-methoxy-phenoxy)-2-(5-methoxy-pyridin-3-yl)-pyrimidine (22g)

Compound 22g was prepared in an analogous manner to that of Compound 21c in Example 21, substituting 3-methoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine for pyridin-3-yl boronic acid in Procedure B of Example 23.

E. {3-(S)-[4-(4-Methoxy-phenoxy)-2-pyridin-3-yl-pyrimidin-5-ylamino]-cyclohexyl}-1-(R)-carbamic acid tert-butyl ester (22h)

To a dry Schlenk tube was added a mixture of Compound 22g (116 mg; 0.34 mmol)), Compound 22f (60 mg; 0.28 mmol), Cs₂CO₃ (182 mg; 0.56 mmol), (diphenylphosphino)ferrocene (54 mg; 0.10 mmol), and tris(dibenzylideneacetone)dipalladium(0) (26 mg; 0.028 mmol). The tube was sealed with a teflon-lined septum, evacuated, and refilled with argon. Dioxane (0.35 mL; reaction conc. >0.75M) was added to the mixture via syringe, and the mixture was heated at 95° C. for 3 h. The resultant mixture was diluted with EtOAc, washed with saturated NH₄Cl (aq) and H₂O. The organic phase was washed sequentially with H₂O, and then dried over Na₂SO₄. The mixture was filtered and the filtrate was concentrated under reduced pressure to give a crude material. The crude material was purified by flash column chromatography (SiO₂), eluting with a heptane-EtOAc gradient to afford Compound 22h (110 mg; 93% yield). ¹H-NMR (400 MHz, CDCl₃): δ 8.84 (d, 1H), 8.24 (d, 1H), 8.01 (s, 1H), 7.89-7.90 (m, 1H), 7.14-7.18 (m, 1H), 6.94-6.98 (m, 2H), 4.48-4.50 (m, 1H), 4.23-4.25 (m, 1H), 3.86 (s, 6H), 3.62 (br. s, 1H), 3.43-3.51 (m, 1H), 2.52-2.55 (m, 1H), 2.20-2.23 (m, 1H), 2.04-2.07 (m, 1H), 1.89-1.94 (m, 1H), 1.46 (s, 9H), 1.41-1.46 (m, 1H), 1.08-1.21 (m, 3H); MS: m/z 522.2 (M+H)⁺.

E. Cpd 312: N-[4-(4-Methoxy-phenoxy)-2-(5-methoxy-pyridin-3-yl)-pyrimidin-5-yl]-cyclohexane-(1R,3S)-1,3-diamine

Using an adaptation of the method described in Procedure E of Example 1, substituting Compound 22h for Compound 1g, the title Compound 312 was obtained as a HCl salt (92 mg). Free base-¹H-NMR (400 MHz, CDCl₃): δ 8.86 (s, 1H), 8.24 (d, 1H), 7.99 (s, 1H), 7.88-7.89 (m, 1H), 7.16-7.19 (m, 2H), 6.95-6.98 (m, 2H), 4.44-4.46 (m, 1H), 3.87 (s, 3H), 3.86 (s, 3H), 3.43-3.51 (m, 1H), 2.89-2.95 (m, 1H), 2.34-2.37 (m, 1H), 2.15-2.19 (m, 1H), 1.88-1.95 (m, 2H), 1.41-1.51 (m, 3H), 1.10-1.26 (m, 3H); MS: m/z 422.0 (M+H)⁺.

Following the procedure described above for Example 22 and substituting the appropriate reagents, starting materials and purification methods known to those skilled in the art, the following compounds of the present invention were prepared:

Cpd 311

The title compound was prepared in an analogous manner to Compound 312 of Example 22, substituting Compound 22e for Compound 22d in Procedure C. Free base-¹H-NMR (400 MHz, CDCl₃): δ 8.86 (d, 1H), 8.24 (d, 1H), 7.99 (s, 1H), 7.88-7.89 (m, 1H), 7.15-7.20 (m, 2H), 6.94-6.98 (m, 2H), 4.44-4.46 (m, 1H), 3.87 (s, 3H), 3.86 (s, 3H), 3.42-3.51 (m, 1H), 2.89-2.96 (m, 1H), 2.34-2.37 (m, 1H), 2.15-2.18 (m, 1H), 1.88-1.95 (m, 2H), 1.40-1.51 (m, 3H), 1.10-1.25 (m, 3H); MS: m/z 422.0 (M+H)⁺.

Cpd 316

The title compound was prepared in an analogous manner to Compound 312 of Example 22, substituting 5-chloro-4-(4-methoxy-phenoxy)-2-(5-methylsulfanyl-pyridin-3-yl)-pyrimidine (prepared in a same manner to Compound 21c of Example 21, substituting 5-(methylthio)pyridine-3-boronic acid for pyridin-3-yl boronic acid in Procedure B) for Compound 22g in Procedure D. Free base-¹H-NMR (400 MHz, CDCl₃): δ 8.99 (d, 1H), 8.40 (d, 1H), 8.20-8.21 (m, 1H), 7.98 (s, 1H), 7.14-7.18 (m, 2H), 6.94-6.98 (m, 2H), 4.47-4.49 (m, 1H), 3.86 (s, 3H), 3.41-3.51 (m, 1H), 2.87-2.94 (m, 1H), 2.47 (s, 3H), 2.32-2.35 (m, 1H), 2.14-2.17 (m, 1H), 1.87-1.92 (m, 2H), 1.37-1.50 (m, 3H), 1.08-1.27 (m, 3H); MS: m/z 438.2 (M+H)⁺.

Example 23

A. Cpd 355: 4-(4-Methoxy-phenoxy)-5-(4-methyl-piperazin-1-yl)-2-pyridin-3-yl-pyrimidine

Using an adaptation of the method described in Procedure D of Example 22 check to see if this method is present in examples, substituting 1-methyl-piperazine for piperazine-1-carboxylic acid tert-butyl ester, the title Compound 355 was obtained as a free base. HCl salt-¹H-NMR (400 MHz, DMSO-d₆): δ 11.24 (br. s, 1H), 9.12 (d, 1H), 8.81 (dd, 1H), 8.64 (d, 1H), 8.54 (s, 1H), 7.87 (dd, 1H), 7.26-7.30 (m, 2H), 7.03-7.08 (m, 2H), 3.86-3.91 (m, 2H), 3.81 (s, 3H), 3.52-3.55 (m, 2H), 3.22-3.40 (m, 4H), 2.83 (d, 3H); MS: m/z 378.0 (M+H)⁺.

Following the procedure described above for Example 23 and substituting the appropriate reagents, starting materials and purification methods known to those skilled in the art, the following compounds of the present invention were prepared:

Cpd MS (M + H)⁺ 297 352.0 359 392.3

Example 24

A. 5-Bromo-2-(5-cyano-pyridin-3-yl)-4-(4-methoxy-phenoxy)-pyrimidine (24a)

Using an adaptation of the method described in Procedure C of Example 22, substituting 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-nicotinonitrile for pyridin-3-yl boronic acid, the title Compound 24a was obtained as white powder. ¹H-NMR (400 MHz, CDCl₃): δ 9.50 (d, 1H), 8.91 (d, 1H), 8.80 (s, 1H), 8.69 (t, 1H), 7.14 (d, 2H), 6.99 (d, 2H), 3.88 (s, 3H); MS: m/z 383.0 (M+H)⁺.

B. Cpd 335: 5-[4-(4-Methoxy-phenoxy)-5-(3-oxo-piperazin-1-yl)-pyrimidin-2-yl]-nicotinonitrile

Using an adaptation of the method described in Procedure D of Example 22, substituting Compound 24a for Compound 22d and substituting piperazin-2-one for piperazine-1-carboxylic acid tert-butyl ester, the title Compound 335 (10% yield) was obtained as a free base after purification by preparative TLC. ¹H-NMR (400 MHz, CDCl₃): δ 9.44 (d, 1H), 8.84 (d, 1H), 8.63 (t, 1H), 8.24 (s, 1H), 7.12 (d, 2H), 6.98 (d, 2H), 6.03 (br. s, 1H), 4.04 (s, 2H), 3.88 (s, 3H), 3.61-3.64 (m, 4H); MS: m/z 403.0 (M+H)⁺.

Example 25

A. 4-[2-(5-Cyano-pyridin-3-yl)-4-(4-methoxy-phenoxy)-pyrimidin-5-yl]-3-oxo-piperazine-1-carboxylic acid tert-butyl ester (25a)

Using an adaptation of the method described in Procedure D of Example 22, substituting Compound 24a for Compound 22d, substituting 3-oxo-piperazine-1-carboxylic acid tert-butyl ester for piperazine-1-carboxylic acid tert-butyl ester and substituting Xantphos for (diphenylphosphino)ferrocene, the title Compound 25a (85% yield) was obtained. ¹H-NMR (400 MHz, CDCl₃): δ 9.51 (d, 1H), 8.90 (d, 1H), 8.71 (t, 1H), 8.65 (s, 1H), 7.11 (d, 2H), 6.97 (d, 2H), 4.34 (s, 2H), 3.88 (s, 3H), 3.87-3.90 (m, 2H), 3.82-3.85 (m, 2H); MS: m/z 503.0 (M+H)⁺.

B. Cpd 337: 5-[4-(4-Methoxy-phenoxy)-5-(2-oxo-piperazin-1-yl)-pyrimidin-2-yl]-nicotinonitrile

To a solution of Compound 24a in CH₂Cl₂ (3 mL) was added TFA (1 mL). The reaction was stirred at room temperature for 3 h and the solvent was evaporated in vacuo to give the crude material. The crude material was purified by preparative TLC to afford Compound 337 as a TFA salt. ¹H-NMR (400 MHz, CDCl₃): δ 9.52 (d, 1H), 8.93 (d, 1H), 8.74 (t, 1H), 8.68 (s, 1H), 7.09 (d, 2H), 6.98 (d, 2H), 4.11 (br. s, 4H), 3.87 (s, 3H), 3.72 (br. s, 2H); MS: m/z 403.0 (M+H)⁺.

Example 26

A. 2-(S)-{[2-(5-Formyl-pyridin-3-yl)-4-(4-methoxy-phenoxy)-pyrimidin-5-ylamino]-methyl}-pyrrolidine-1-carboxylic acid tert-butyl ester (26a)

The title compound was prepared in an analogous manner to Compound 1g of Example 1, substituting 5-formylpyridin-3-yl boronic acid for Compound 1f in Procedure D.

B. 2-(S)-{[2-(5-Hydroxymethyl-pyridin-3-yl)-4-(4-methoxy-phenoxy)-pyrimidin-5-ylamino]-methyl}-pyrrolidine-1-carboxylic acid tert-butyl ester (26b)

To a solution of Compound 26a (200 mg, 0.40 mmol) in THF (5 mL) at 0° C. was added LiBH₄ solution (2.0 M in THF) (0.3 mL) dropwise. The reaction mixture was stirred at 0° C. for 0.5 h, then warmed to room temperature over 2 h. The resultant mixture was diluted with water. The mixture was extracted with EtOAc (3×), and the organic phases were combined, dried over Na₂SO₄, and concentrated under reduced pressure to give the crude material. The crude material was purified by flash column chromatography (SiO₂), eluting with a heptane-EtOAc gradient to afford Compound 26b (71.5 mg; 35% yield). ¹H-NMR (400 MHz, CDCl₃): δ 9.00 (s, 1H), 8.43 (s, 1H), 8.39 (s, 1H), 7.80-7.94 (m, 1H), 7.13-7.16 (m, 2H), 6.91-6.94 (m, 2H), 5.83 (br. s, 0.6H), 5.06 (br. s, 0.4H), 4.71 (s, 2H), 4.18-4.26 (m, 1H), 3.84 (s, 3H), 3.86 (br. s, 0.6H), 3.50 (br. s, 0.4H), 3.37-3.40 (m, 2H), 3.15-3.20 (m, 2H), 2.06-2.15 (m, 1H), 1.90-1.98 (m, 2H), 1.77-1.86 (m, 1H), 1.43-1.49 (m, 9H); MS: m/z 508.2 (M+H)⁺.

C. Cpd 269: (5-{4-(4-Methoxy-phenoxy)-5-[(pyrrolidin-2-(S)-ylmethyl)-amino]-pyrimidin-2-yl}-pyridin-3-yl)-methanol

To a solution of Compound 26b (71.5 mg) in dichloromethane (2 mL) was treated with TFA (1 mL) at room temperature for 2 h. The reaction mixture was adjusted to pH 12 with 1 N NaOH (aq). The resultant mixture was extracted with CH₂Cl₂ (3×). The organic extracts were combined, dried over Na₂SO₄, and concentrated under reduced pressure to give the free base (52 mg). The free base was dissolved in CH₂Cl₂ (2 mL), and treated with 1.0 M HCl in Et₂O (0.25 mL) at ambient temperature for 2 h. A solid was collected and dried by vacuum filtration to afford Compound 269 as a HCl salt. Free base-¹H-NMR (400 MHz, MeOH-d₄): δ 8.95-9.05 (m, 1H), 8.55-8.70 (m, 1H), 8.36-8.42 (m, 1H), 8.06-8.11 (m, 1H), 7.15-7.21 (m, 2H), 6.98-7.02 (m, 2H), 4.72 (s, 1H), 4.63 (s, 1H), 3.83 (d, 3H), 3.74-3.83 (m, 1H), 3.45-3.58 (m, 2H), 3.13-3.28 (m, 2H), 2.15-2.25 (m, 1H), 1.93-2.08 (m, 2H), 1.68-1.79 (m, 1H); MS: m/z 408.2 (M+H)⁺.

Example 27

A. 4-(R)-(tert-Butyl-dimethyl-silanyloxy)-pyrrolidine-2-(S)-1,2 dicarboxylic acid 1-tert-butyl ester 2-methyl ester (27b)

A solution of Compound 27a (2.64 g; 10.8 mmol) in DMF (12 mL) was treated with t-butyl-dimethyl silylchloride (1.78 g; 11.84 mmol) and imidazole (1.2 g; 17.64 mmol) at room temperature for 2 h. The resultant mixture was concentrated in vacuuo and partitioned between EtOAc and H₂O. The organic phase was washed sequentially with 0.1 N HCl (aq), saturated NaHCO₃ (aq), and brine, and then dried over Na₂SO₄. The mixture was filtered and the filtrate was evaporated under reduced pressure to give the crude material. The crude material was purified by flash column chromatography (SiO₂), eluting with a heptane-EtOAc gradient to afford Compound 27b. ¹H-NMR (400 MHz, CDCl₃): δ 4.32-4.45 (m, 2H), 3.74-3.75 (d, 3H), 3.58-3.64 (m, 1H), 3.32-3.43 (m, 1H), 2.16-2.19 (m, 1H), 2.00-2.06 (m, 1H), 1.42-1.47 (d, 9H), 0.88 (s, 9H), 0.07 (s, 6H). MS: m/z 360.2 (M+H)⁺.

B. 4-(R)-(tert-Butyl-dimethyl-silanyloxy)-2-(S)-hydroxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (27c)

To a solution of Compound 27b (392 mg; 1.09 mmol) in THF/MeOH (3/3 mL) at 0° C. was added NaBH₄ (148 mg; 3.92 mmol) and LiCl (166 mg; 3.92 mmol). The reaction mixture was stirred at 0° C. for 0.5 h, then warmed to room temperature over 2 h. The resultant mixture was diluted with 0.5N HCl (aq). The mixture was extracted with EtOAc (3×), the organic extracts were combined, dried over Na₂SO₄, and concentrated under reduced pressure to give the crude material. The crude material was purified by flash column chromatography (SiO₂), eluting with a heptane-EtOAc gradient to afford Compound 27c (345 mg; 95% yield). ¹H-NMR (400 MHz, CDCl₃): δ 4.90 (br. s, 1H), 4.28 (m, 1H), 4.10-4.16 (m, 1H), 3.69-3.72 (m, 1H), 3.53-3.57 (m, 1H), 3.43-3.46 (m, 1H), 3.33-3.37 (m, 1H), 1.94-1.98 (m, 1H), 1.53-1.63 (m, 1H), 1.48 (s, 9H), 0.88 (s, 9H), 0.07 (s, 6H); MS: m/z 332.2 (M+H)⁺.

C. 4-(R)-(tert-Butyl-dimethyl-silanyloxy)-2-(S)-formyl-pyrrolidine-1-carboxylic acid tert-butyl ester (27d)

To a solution of oxalyl chloride (0.16 mL; 1.785 mmol) in CH₂Cl₂ (2 mL) at −78° C. was added DMSO (0.25 mL; 3.55 mmol) dropwise and the mixture was stirred for 10 min. The mixture was then treated with a solution of Compound 27c (395 mg; 1.19 mmol) in CH₂Cl₂ (3 mL) dropwise and continually stirred for 20 min. To the resultant mixture was added Et₃N (0.5 mL; 3.55 mmol) dropwise and the mixture was stirred at −78° C. for 30 min. The mixture was allowed to warm to ambient temperature while continually stirring over 20 min. The reaction mixture was quenched with saturated NH₄Cl (aq), extracted with EtOAc, washed with water and brine; and the combined organic extracts were dried over Na₂SO₄, and concentrated under reduced pressure to give the crude material. The crude material was purified by flash column chromatography (SiO₂), eluting with a heptane-EtOAc gradient to afford Compound 27d (250 mg; 64% yield). ¹H-NMR (400 MHz, CDCl₃): δ 9.44-9.57 (m, 1H), 4.20-4.39 (m, 1H), 3.35-3.57 (m, 1H), 1.89-2.09 (m, 1H), 1.44-1.49 (m, 9H), 0.88 (s, 9H), 0.08 (s, 6H); MS: m/z 330.2 (M+H)⁺.

D. 4-(R)-(tert-Butyl-dimethyl-silanyloxy)-2-(S)-{[2-chloro-4-(4-methoxy-phenoxy)-pyrimidin-5-ylamino]-methyl}-pyrrolidine-1-carboxylic acid tert-butyl ester (27e)

To a solution of Compound 1c (191 mg, 0.759 mmol) in 1,2-dichloroethane (4 mL) was added Compound 27d (250 mg; 0.759 mmol) and acetic acid (0.2 mL) at ambient temperature, and the mixture was stirred at room temperature for 1.5 h. The mixture was then treated with NaB(OAc)₃H (240 mg; 1.14 mmol) and continually stirred at room temperature for 4 h. The resultant mixture was diluted with CH₂Cl₂, then washed with saturated NaHCO₃ (aq) and water. The organic phase was washed sequentially with water and brine, and then dried over Na₂SO₄. The mixture was filtered and the filtrate was evaporated under reduced pressure to give the crude material. The crude material was purified by flash column chromatography (SiO₂), eluting with a heptane-EtOAc gradient to afford Compound 27e. ¹H-NMR (400 MHz, CDCl₃): δ 7.70-7.75 (m, 1H), 7.10-7.13 (m, 2H), 6.94-7.01 (m, 2H), 5.79 (br. s, 0.6H), 4.73 (br. s, 0.4H), 4.30-4.39 (m, 2H), 3.84 (s, 3H), 3.12-3.69 (m, 4H), 2.06-2.16 (m, 1H), 1.80-1.87 (m, 1H), 1.45-1.48 (m, 9H), 0.88 (s, 9H), 0.08 (s, 6H); MS: m/z 565.2 (M+H)⁺.

E. 4-(R)-(tert-Butyl-dimethyl-silanyloxy)-2-{[4-(4-methoxy-phenoxy)-2-(S)-(pyridin-3-O-pyrimidin-5-ylamino]-methyl}-pyrrolidine-1-carboxylic acid tert-butyl ester (27f)

To a teflon-lined septum sealed Schlenk tube, a mixture of Compound 27e (130 mg; 0.23 mmol), pyridin-3-yl boronic acid (56.5 mg; 0.46 mmol), K₂CO₃ (64 mg; 0.46 mmol) and [1,1′-bis(diphenylphosphino)-ferrocene]dichloro-palladium(II) (11.3 mg, 0.014 mmol) in a mixture of ethanol (0.5 mL) and H₂O (0.1 mL) was added. The reaction mixture was irradiated in a microwave instrument at 130° C. for 30 min. The resultant mixture was diluted with EtOAc, then washed with saturated NH₄Cl (aq) and water. The organic phase was washed with H₂O, and then dried over Na₂SO₄. The mixture was filtered and the filtrate was evaporated under reduced pressure to give the crude material. The crude material was purified by flash column chromatography (SiO₂), eluting with a heptane-EtOAc gradient to afford Compound 27f (100 mg; 71% yield). ¹H-NMR (400 MHz, CDCl₃): δ 9.27 (s, 1H), 8.52-8.53 (m, 1H), 8.33-8.35 (m, 1H), 7.99-8.02 (m, 1H), 7.26-7.28 (m, 1H), 7.13-7.19 (m, 2H), 6.95-6.97 (m, 2H), 5.77 (br. s, 0.6H), 4.84 (br. s, 0.4H), 4.35-4.42 (m, 2H), 3.87 (s, 3H), 3.28-3.69 (m, 4H), 2.12-2.18 (m, 1H), 1.86-1.91 (m, 1H), 1.47-1.51 (m, 9H), 0.88 (s, 9H), 0.08 (s, 6H); MS: m/z 608.1 (M+H)⁺.

F. Cpd 270: 5-(S)-{[4-(4-Methoxy-phenoxy)-2-(pyridin-3-yl)-pyrimidin-5-ylamino]-methyl}-pyrrolidin-3-(R)-ol

Compound 27f (100 mg; 0.165 mmol) in trifluoroacetic acid (1 mL) was stirred at room temperature 20 h. The reaction mixture was adjusted to pH 12 by the addition of 1 N NaOH (aq). The resultant mixture was extracted with CH₂Cl₂ and H₂O. The organic phase was washed with H₂O and dried over Na₂SO₄. The mixture was then filtered, and the filtrate was concentrated under reduced pressure. The residue was dissolved in CH₂Cl₂ (3 mL), treated with 1.0 M HCl in Et₂O (0.33 mL; 0.33 mmol) at ambient temperature, and the reaction mixture was stirred for 20 h. The mixture was evaporated in vacuo, and the reside was triturated with Et₂O. A solid was collected and dried by vacuum filtration to afford Compound 270 (63 mg; 81% yield) as a HCl salt. Cpd 270 (free base) ¹H-NMR (400 MHz, CDCl₃): δ 9.26 (d, 1H), 8.53 (dd, 1H), 8.32 (dt, 1H), 7.99 (s, 1H), 7.24-7.27 (m, 1H), 7.15-7.19 (m, 2H), 6.95-6.99 (m, 2H), 4.85-4.88 (m, 1H), 4.54-4.55 (m, 1H), 3.88 (s, 3H), 3.82-3.88 (m, 2H), 3.28-3.34 (m, 1H), 3.06-3.13 (m, 1H), 3.03-3.04 (m, 2H), 2.04-2.09 (m, 1H), 1.73-1.80 (m, 1H), 1.6 (br. s, 1H); MS: m/z 394.0 (M+H)⁺.

Following the procedure described above for Example 27 and substituting the appropriate reagents, starting materials and purification methods known to those skilled in the art, the following compounds of the present invention were prepared:

Cpd MS (M + H)⁺ Cpd MS (M + H)⁺ 271 394.0 272 394.0

Example 28

A. 4-(R)-(tert-Butyl-dimethyl-silanyloxy)-2-{[2-chloro-4-(4-methoxy-phenoxy)-pyrimidin-5-ylamino]-methyl}-pyrrolidine-1-carboxylic acid tert-butyl ester (28b)

Using an adaptation of the method described in Procedure D of Example 27, substituting Compound 28a (commercially available) for Compound 27d, the title Compound 28b was obtained. ¹H-NMR (400 MHz, CDCl₃): δ 7.70-7.75 (m, 1H), 7.06-7.13 (m, 2H), 6.91-6.95 (m, 2H), 5.74-5.79 (m, 0.6H), 4.73-4.82 (m, 0.4H), 4.38-4.44 (m, 2H), 3.83 (s, 3H), 3.12-3.69 (m, 4H), 2.10-2.24 (m, 1H), 1.78-1.88 (m, 1H), 1.44-1.48 (m, 9H), 0.88-0.92 (m, 9H), 0.08-0.10 (m, 6H); MS: m/z 565.0 (M+H)⁺.

B. 4-(R)-(tert-Butyl-dimethyl-silanyloxy)-2-{[4-(4-methoxy-phenoxy)-2-(S)-(5-methoxy-pyridin-3-yl)-pyrimidin-5-ylamino]-methyl}-pyrrolidine-1-carboxylic acid tert-butyl ester (34c) and 4-(R)-(tert-Butyl-dimethyl-silanyloxy)-2-{[4-(4-methoxy-phenoxy)-2-(R)-(5-methoxy-pyridin-3-yl)-pyrimidin-5-ylamino]-methyl}-pyrrolidine-1-carboxylic acid tert-butyl ester (28d)

Using an adaptation of the method described in Procedure E of Example 27, substituting Compound 28b for Compound 27e and substituting 3-methoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine for pyridin-3-yl boronic acid, the title Compound 28c and Compound 28d were obtained separately after flash column chromatography (SiO₂). Compound 28c-¹H-NMR (400 MHz, CDCl₃): δ 8.87 (s, 1H), 8.24 (s, 1H), 7.98 (s, 1H), 7.89 (s, 1H), 7.13-7.20 (m, 2H), 6.94-6.96 (m, 2H), 5.78 (br. s, 0.6H), 4.86 (br. s, 0.4H), 4.34-4.42 (m, 2H), 3.86 (s, 6H), 3.29-3.51 (m, 4H), 2.12-2.18 (m, 1H), 1.86-1.94 (m, 1H), 1.47-1.51 (m, 9H), 0.87-0.89 (m, 9H), 0.08 (s, 6H); MS: m/z 638.2 (M+H)⁺. Compound 28d-¹H-NMR (400 MHz, CDCl₃): δ 8.86 (br. s, 1H), 8.23 (br. s, 1H), 7.98-7.99 (m, 1H), 7.89 (s, 1H), 7.12-7.20 (m, 2H), 6.92-6.96 (m, 2H), 5.84 (br. s, 0.6H), 4.97 (br. s, 0.4H), 4.27-4.43 (m, 2H), 3.85 (s, 6H), 3.57-3.81 (m, 2H), 3.29-3.39 (m, 2H), 2.18-2.25 (m, 1H), 1.82-1.91 (m, 1H), 1.45-1.50 (m, 9H), 0.91-0.92 (m, 9H), 0.10-0.11 (m, 6H); MS: m/z 638.2 (M+H)⁺.

C. Cpd 273: 5-(S)-{[4-(4-Methoxy-phenoxy)-2-(5-methoxy-pyridin-3-yl)-pyrimidin-5-ylamino]-methyl}-pyrrolidin-3-(R)-ol

Using an adaptation of the method described in Procedure F of Example 27, substituting Compound 28c for Compound 27f, the title Compound 273 was obtained as a HCl salt. Cpd 273, free base-¹H-NMR (400 MHz, CDCl₃): δ 8.87 (d, 1H), 8.25 (d, 1H), 8.00 (s, 1H), 7.89 (dd, 1H), 7.16-7.20 (m, 2H), 6.94-6.98 (m, 2H), 4.83-4.86 (m, 1H), 4.53-4.55 (m, 1H), 3.87 (s, 3H), 3.86 (s, 3H), 3.79-3.87 (m, 1H), 3.26-3.32 (m, 1H), 3.04-3.11 (m, 1H), 3.01-3.02 (m, 2H), 2.02-2.08 (m, 1H), 1.72-1.79 (m, 1H), 1.25-1.27 (m, 1H); MS: m/z 424.0 (M+H)⁺.

D. Cpd 274: 5-(R)-{[4-(4-Methoxy-phenoxy)-2-(5-methoxy-pyridin-3-yl)-pyrimidin-5-ylamino]-methyl}-pyrrolidin-3-(R)-ol

Using an adaptation of the method described in Procedure F of Example 27, substituting Compound 28d for Compound 27f, the title Compound 274 was obtained as a HCl salt. Free base-¹H-NMR (400 MHz, CDCl₃): δ 8.85 (d, 1H), 8.24 (d, 1H), 7.99 (s, 1H), 7.88 (dd, 1H), 7.16-7.20 (m, 2H), 6.93-6.97 (m, 2H), 5.08-5.10 (m, 1H), 4.46-4.50 (m, 1H), 3.86 (s, 3H), 3.86 (s, 3H), 3.62-3.69 (m, 1H), 3.42-3.49 (m, 1H), 3.31-3.38 (m, 1H), 3.01-3.14 (m, 2H), 2.28-2.37 (m, 1H), 1.66-1.73 (m, 1H), 1.25-1.27 (m, 1H); MS: m/z 424.0 (M+H)⁺.

Following the procedure described above for Example 28 and substituting the appropriate reagents, starting materials and purification methods known to those skilled in the art, the following compounds of the present invention were prepared:

Compounds 1 through 319, and 321 through 323 of Formula (I) in the table below were synthesized using the procedures described above.

TABLE 1

Cpd Stereo No R₁ R₂ A-L- a L R_(a) Chem 1 4-methoxy-phenyl 4-methoxy-phenyl a₁-L₁ pyrrolidin-2-yl methyl H 2S 2 phenyl 4-methoxy-phenyl a₁-L₁ pyrrolidin-2-yl methyl H 2S 3 3-methoxy-phenyl 4-methoxy-phenyl a₁-L₁ pyrrolidin-2-yl methyl H 2S 4 2-methoxy-phenyl 4-methoxy-phenyl a₁-L₁ pyrrolidin-2-yl methyl H 2S 5 naphth-1-yl 4-methoxy-phenyl a₁-L₁ pyrrolidin-2-yl methyl H 2S 6 naphth-2-yl 4-methoxy-phenyl a₁-L₁ pyrrolidin-2-yl methyl H 2S 7 pyridin-4-yl 4-methoxy-phenyl a₁-L₁ pyrrolidin-2-yl methyl H 2S 8 pyridin-3-yl 4-methoxy-phenyl a₁-L₁ pyrrolidin-2-yl methyl H 2S 9 thien-3-yl 4-methoxy-phenyl a₁-L₁ pyrrolidin-2-yl methyl H 2S 10 furan-3-yl 4-methoxy-phenyl a₁-L₁ pyrrolidin-2-yl methyl H 2S 11 pyridin-3-yl 4-trifluoromethoxy-phenyl a₁-L₁ pyrrolidin-2-yl methyl H 2S 12 pyridin-3-yl 4-aminocarbonyl-phenyl a₁-L₁ pyrrolidin-2-yl methyl H 2S 13 pyridin-3-yl 4-methylcarbonylamino- a₁-L₁ pyrrolidin-2-yl methyl H 2S phenyl 14 pyridin-3-yl phenyl a₁-L₁ pyrrolidin-2-yl methyl H 2S 15 3-hydroxy-phenyl 4-methoxy-phenyl a₁-L₁ pyrrolidin-2-yl methyl H 2S 16 quinolin-5-yl 4-methoxy-phenyl a₁-L₁ pyrrolidin-2-yl methyl H 2S 17 quinolin-8-yl 4-methoxy-phenyl a₁-L₁ pyrrolidin-2-yl methyl H 2S 18 2-methyl-quinolin-5-yl 4-methoxy-phenyl a₁-L₁ pyrrolidin-2-yl methyl H 2S 19 4-biphenyl 4-methoxy-phenyl a₁-L₁ pyrrolidin-2-yl methyl H 2S 20 quinolin-3-yl 4-methoxy-phenyl a₁-L₁ pyrrolidin-2-yl methyl H 2S 21 dibenzothiophen-2-yl 4-methoxy-phenyl a₁-L₁ pyrrolidin-2-yl methyl H 2S 22 6-methoxy-pyridin- 4-methoxy-phenyl a₁-L₁ pyrrolidin-2-yl methyl H 2S 3-yl 23 pyrimidin-5-yl 4-methoxy-phenyl a₁-L₁ pyrrolidin-2-yl methyl H 2S 24 2-fluoro-pyridin-3-yl 4-methoxy-phenyl a₁-L₁ pyrrolidin-2-yl methyl H 2S 25 6-fluoro-pyridin-3-yl 4-methoxy-phenyl a₁-L₁ pyrrolidin-2-yl methyl H 2S 26 2-methoxy-pyridin- 4-methoxy-phenyl a₁-L₁ pyrrolidin-2-yl methyl H 2S 3-yl 27 2,6- 4-methoxy-phenyl a₁-L₁ pyrrolidin-2-yl methyl H 2S dihydroxypyrimidin- 5-yl 28 3-cyano-phenyl 4-methoxy-phenyl a₁-L₁ pyrrolidin-2-yl methyl H 2S 29 3-nitro-phenyl 4-methoxy-phenyl a₁-L₁ pyrrolidin-2-yl methyl H 2S 30 3-aminocarbonyl- 4-methoxy-phenyl a₁-L₁ pyrrolidin-2-yl methyl H 2S phenyl 31 3-N,N- 4-methoxy-phenyl a₁-L₁ pyrrolidin-2-yl methyl H 2S diethylaminocarbonyl- phenyl 32 3-methanesulfonyl- 4-methoxy-phenyl a₁-L₁ pyrrolidin-2-yl methyl H 2S phenyl 33 4-hydroxy-phenyl 4-methoxy-phenyl a₁-L₁ pyrrolidin-2-yl methyl H 2S 34 indol-5-yl 4-methoxy-phenyl a₁-L₁ pyrrolidin-2-yl methyl H 2S 35 4H-[1,2,4]oxadiazol- 4-methoxy-phenyl a₁-L₁ pyrrolidin-2-yl methyl H 2S 5-on-3-yl 36 pyridin-3-yl 4-fluoro-phenyl a₁-L₁ pyrrolidin-2-yl methyl H 2S 37 6-methoxy-pyridin- 4-fluoro-phenyl a₁-L₁ pyrrolidin-2-yl methyl H 2S 3-yl 38 3-fluoro-phenyl 4-methoxy-phenyl a₁-L₁ pyrrolidin-2-yl methyl H 2S 39 6-methoxy-pyridin- 2-methoxy-phenyl a₁-L₁ pyrrolidin-2-yl methyl H 2S 3-yl 40 pyridin-3-yl 2-methoxy-phenyl a₁-L₁ pyrrolidin-2-yl methyl H 2S 41 3-diethylamino- 4-methoxy-phenyl a₁-L₁ pyrrolidin-2-yl methyl H 2S phenyl 42 3- 4-methoxy-phenyl a₁-L₁ pyrrolidin-2-yl methyl H 2S methylcarbonylamino- phenyl 43 4- 4-methoxy-phenyl a₁-L₁ pyrrolidin-2-yl methyl H 2S methylcarbonylamino- phenyl 44 6-methoxy-pyridin- 4-amino-phenyl a₁-L₁ pyrrolidin-2-yl methyl H 2S 3-yl 45 3-amino-phenyl 4-methoxy-phenyl a₁-L₁ pyrrolidin-2-yl methyl H 2S 46 pyridin-3-yl 4-amino-phenyl a₁-L₁ pyrrolidin-2-yl methyl H 2S 47 benzothiazol-2-yl 4-methoxy-phenyl a₁-L₁ pyrrolidin-2-yl methyl H 2S 48 thiazol-2-yl 4-methoxy-phenyl a₁-L₁ pyrrolidin-2-yl methyl H 2S 49 benzothiophen-2-yl 4-methoxy-phenyl a₁-L₁ pyrrolidin-2-yl methyl H 2S 50 3-trifluoromethyl- 4-methoxy-phenyl a₁-L₁ pyrrolidin-2-yl methyl H 2S phenyl 51 3-trifluoromethoxy- 4-methoxy-phenyl a₁-L₁ pyrrolidin-2-yl methyl H 2S phenyl 52 2-methylthio- 4-methoxy-phenyl a₁-L₁ pyrrolidin-2-yl methyl H 2S pyrimidin-5-yl 53 2-methoxy- 4-methoxy-phenyl a₁-L₁ pyrrolidin-2-yl methyl H 2S pyrimidin-5-yl 54 5-fluoro-pyridin-3-yl 4-methoxy-phenyl a₁-L₁ pyrrolidin-2-yl methyl H 2S 55 3,5-difluoro-phenyl 4-methoxy-phenyl a₁-L₁ pyrrolidin-2-yl methyl H 2S 56 3,4-difluoro-phenyl 4-methoxy-phenyl a₁-L₁ pyrrolidin-2-yl methyl H 2S 57 3,5-difluoro-4- 4-methoxy-phenyl a₁-L₁ pyrrolidin-2-yl methyl H 2S hydroxymethyl-phenyl 58 2,4-dimethoxy- 4-methoxy-phenyl a₁-L₁ pyrrolidin-2-yl methyl H 2S pyrimidin-5-yl 59 6-methoxy-pyridin-3- 4-hydroxy-phenyl a₁-L₁ pyrrolidin-2-yl methyl H 2S yl 60 2-ethoxy-pyrimidin- 4-methoxy-phenyl a₁-L₁ pyrrolidin-2-yl methyl H 2S 5-yl 61 pyrazol-5-yl 4-methoxy-phenyl a₁-L₁ pyrrolidin-2-yl methyl H 2S 62 3,5-dimethyl-isoxazol- 4-methoxy-phenyl a₁-L₁ pyrrolidin-2-yl methyl H 2S 4-yl 63 2,3- 4-methoxy-phenyl a₁-L₁ pyrrolidin-2-yl methyl H 2S dihydrobenzofuran- 5-yl 64 3-fluoro-4-methoxy- 4-methoxy-phenyl a₁-L₁ pyrrolidin-2-yl methyl H 2S phenyl 65 pyrazol-4-yl 4-methoxy-phenyl a₁-L₁ pyrrolidin-2-yl methyl H 2S 66 2-methylthio- 4-methoxy-phenyl a₁-L₁ pyrrolidin-2-yl methyl H 2S pyrimidin-4-yl 67 1-methyl-pyrazol-4-yl 4-methoxy-phenyl a₁-L₁ pyrrolidin-2-yl methyl H 2S 68 5-methoxy-pyridin- 4-methoxy-phenyl a₁-L₁ pyrrolidin-2-yl methyl H 2S 3-yl 69 5-cyano-pyridin-3-yl 4-methoxy-phenyl a₁-L₁ pyrrolidin-2-yl methyl H 2S 70 3-fluoro-5-methoxy- 4-methoxy-phenyl a₁-L₁ pyrrolidin-2-yl methyl H 2S phenyl 71 3-fluoro-5-methyl- 4-methoxy-phenyl a₁-L₁ pyrrolidin-2-yl methyl H 2S phenyl 72 6-amino-pyridin-3-yl 4-methoxy-phenyl a₁-L₁ pyrrolidin-2-yl methyl H 2S 73 5-fluoro-6-methoxy- 4-methoxy-phenyl a₁-L₁ pyrrolidin-2-yl methyl H pyridin-3-yl 74 6-hydroxy-pyridin-3-yl 4-methoxy-phenyl a₁-L₁ pyrrolidin-2-yl methyl H 2S 75 6-hydroxy-pyridin-3-yl 4-hydroxy-phenyl a₁-L₁ pyrrolidin-2-yl methyl H 76 quinoxalin-6-yl 4-methoxy-phenyl a₁-L₁ pyrrolidin-2-yl methyl H 2S 77 1H- 4-methoxy-phenyl a₁-L₁ pyrrolidin-2-yl methyl H 2S pyrrolo[2,3-b]pyridin- 5-yl 78 benzo[1,2,5]oxadiazol- 4-methoxy-phenyl a₁-L₁ pyrrolidin-2-yl methyl H 2S 5-yl 79 pyrimidin-5-yl 4-methoxy-phenyl a₁-L₁ 4,4-difluoro- methyl H 2S pyrrolidin-2-yl 80 pyrimidin-5-yl 4-methoxy-phenyl a₁-L₁ 4-fluoro- methyl H 2S,4R pyrrolidin-2-yl 81 2-amino-pyrimidin- 4-methoxy-phenyl a₁-L₁ pyrrolidin-2-yl methyl H 2S 5-yl 82 2-dimethylamino- 4-methoxy-phenyl a₁-L₁ pyrrolidin-2-yl methyl H 2S pyrimidin-5-yl 83 2-(morpholin-4-yl)- 4-methoxy-phenyl a₁-L₁ pyrrolidin-2-yl methyl H 2S pyrimidin-5-yl 84 2-(4-methyl-pyrazin-1- 4-methoxy-phenyl a₁-L₁ pyrrolidin-2-yl methyl H 2S yl)-pyrimidin-5-yl 85 pyrimidin-5-yl benzothiazol-6-yl a₁-L₁ pyrrolidin-2-yl methyl H 2S 86 5-cyano-pyridin-3-yl benzothiazol-6-yl a₁-L₁ pyrrolidin-2-yl methyl H 2S 87 pyrimidin-5-yl 2-methyl-benzoxazol-6-yl a₁-L₁ pyrrolidin-2-yl methyl H 2S 88 5-cyano-pyridin-3-yl 2-methyl-benzoxazol-6-yl a₁-L₁ pyrrolidin-2-yl methyl H 2S 89 pyrimidin-5-yl 4-methoxy-phenyl a₁-L₁ 4-fluoro- methyl H 2S,4S pyrrolidin-2-yl 90 5-cyano-pyridin-3-yl 2-methyl-benzothiazol-6-yl a₁-L₁ pyrrolidin-2-yl methyl H 2S 91 pyrimidin-5-yl 2-methyl-benzothiazol-6-yl a₁-L₁ pyrrolidin-2-yl methyl H 2S 92 3,5-dimethyl-phenyl 4-methoxy-phenyl a₁-L₁ pyrrolidin-2-yl methyl H 2S 93 benzo[1,3]dioxol-5-yl 4-methoxy-phenyl a₁-L₁ pyrrolidin-2-yl methyl H 2S 94 3,5-dichloro-phenyl 4-methoxy-phenyl a₁-L₁ pyrrolidin-2-yl methyl H 2S 95 6-cyano-pyridin-3-yl 4-methoxy-phenyl a₁-L₁ pyrrolidin-2-yl methyl H 2S 96 5-cyano-pyridin-3-yl 3,5-difluoro-4-methoxy- a₁-L₁ pyrrolidin-2-yl methyl H 2S phenyl 97 pyrimidin-5-yl 3,5-difluoro-4-methoxy- a₁-L₁ pyrrolidin-2-yl methyl H 2S phenyl 98 5-cyano-pyridin-3-yl 3-methoxy-phenyl a₁-L₁ pyrrolidin-2-yl methyl H 2S 99 pyrimidin-5-yl 3-methoxy-phenyl a₁-L₁ pyrrolidin-2-yl methyl H 2S 100 pyridin-3-yl 3-methoxy-phenyl a₁-L₁ pyrrolidin-2-yl methyl H 2S 101 5-cyano-pyridin-3-yl 2,3-difluoro-4-methoxy- a₁-L₁ pyrrolidin-2-yl methyl H 2S phenyl 102 5-fluoro-pyridin-3-yl 2,3-difluoro-4-methoxy- a₁-L₁ pyrrolidin-2-yl methyl H 2S phenyl 103 pyrimidin-5-yl 2,3-difluoro-4-methoxy- a₁-L₁ pyrrolidin-2-yl methyl H 2S phenyl 104 5-cyano-pyridin-3-yl 4-ethoxy-phenyl a₁-L₁ pyrrolidin-2-yl methyl H 2S 105 pyrimidin-5-yl 4-ethoxy-phenyl a₁-L₁ pyrrolidin-2-yl methyl H 2S 106 5-fluoro-pyridin-3-yl 4-ethoxy-phenyl a₁-L₁ pyrrolidin-2-yl methyl H 2S 107 5-methylthio-pyridin- 4-methoxy-phenyl a₁-L₁ pyrrolidin-2-yl methyl H 2S 3-yl 108 5-methanesulfonyl- 4-methoxy-phenyl a₁-L₁ pyrrolidin-2-yl methyl H 2S pyridin-3-yl 109 pyrimidin-5-yl 4-methoxy-phenyl a₁-L₁ piperidin-3-yl absent H racemic 110 5-cyano-pyridin-3-yl 4-difluoromethoxy-phenyl a₁-L₁ pyrrolidin-2-yl methyl H 2S 111 pyrimidin-5-yl 4-difluoromethoxy-phenyl a₁-L₁ pyrrolidin-2-yl methyl H 2S 112 5-fluoro-pyridin-3-yl 4-difluoromethoxy-phenyl a₁-L₁ pyrrolidin-2-yl methyl H 2S 113 5-cyano-pyridin-3-yl 4-n-propyloxy-phenyl a₁-L₁ pyrrolidin-2-yl methyl H 2S 114 pyrimidin-5-yl 4-n-propyloxy-phenyl a₁-L₁ pyrrolidin-2-yl methyl H 2S 115 5-fluoro-pyridin-3-yl 4-n-propyloxy-phenyl a₁-L₁ pyrrolidin-2-yl methyl H 2S 117 indol-4-yl 4-methoxy-phenyl a₁-L₁ pyrrolidin-2-yl methyl H 2S 118 indol-6-yl 4-methoxy-phenyl a₁-L₁ pyrrolidin-2-yl methyl H 2S 119 indol-7-yl 4-methoxy-phenyl a₁-L₁ pyrrolidin-2-yl methyl H 2S 120 pyrazin-2-yl 4-methoxy-phenyl a₁-L₁ pyrrolidin-2-yl methyl H 2S 121 2-cyano-pyrimidin- 4-methoxy-phenyl a₁-L₁ pyrrolidin-2-yl methyl H 2S 5-yl 122 5-cyano-pyridin-3-yl 4-(2,2,2-trifluoro-ethoxy)- a₁-L₁ pyrrolidin-2-yl methyl H 2S phenyl 123 pyrimidin-5-yl 4-(2,2,2-trifluoro-ethoxy)- a₁-L₁ pyrrolidin-2-yl methyl H 2S phenyl 124 5-fluoro-pyridin-3-yl 4-(2,2,2-trifluoro-ethoxy)- a₁-L₁ pyrrolidin-2-yl methyl H 2S phenyl 125 5-cyano-pyridin-3-yl 4-n-butoxy-phenyl a₁-L₁ pyrrolidin-2-yl methyl H 2S 126 pyrimidin-5-yl 4-n-butoxy-phenyl a₁-L₁ pyrrolidin-2-yl methyl H 2S 127 5-fluoro-pyridin-3-yl 4-n-butoxy-phenyl a₁-L₁ pyrrolidin-2-yl methyl H 2S 128 5-fluoro-pyridin-3-yl 4-chloro-phenyl a₁-L₁ pyrrolidin-2-yl methyl H 2S 129 5-cyano-pyridin-3-yl 4-chloro-phenyl a₁-L₁ pyrrolidin-2-yl methyl H 2S 130 pyrimidin-5-yl 4-chloro-phenyl a₁-L₁ pyrrolidin-2-yl methyl H 2S 131 5-fluoro-pyridin-3-yl 3-fluoro-4-methoxy-phenyl a₁-L₁ pyrrolidin-2-yl methyl H 2S 132 5-cyano-pyridin-3-yl 3-fluoro-4-methoxy-phenyl a₁-L₁ pyrrolidin-2-yl methyl H 2S 133 pyrimidin-5-yl 3-fluoro-4-methoxy-phenyl a₁-L₁ pyrrolidin-2-yl methyl H 2S 134 5-cyano-pyridin-3-yl 4-methoxy-phenyl a₁-L₁ 4-fluoro- methyl H 2S,4R pyrrolidin-2-yl 135 pyridin-3-yl 3-cyano-phenyl a₁-L₁ pyrrolidin-2-yl methyl H 2S 136 pyridin-3-yl 4-cyano-phenyl a₁-L₁ pyrrolidin-2-yl methyl H 2S 137 pyridin-3-yl 3-fluoro-4-cyano-phenyl a₁-L₁ pyrrolidin-2-yl methyl H 2S 138 pyridin-3-yl 4- a₁-L₁ pyrrolidin-2-yl methyl H 2S cyclopropylcarbonylamino- phenyl 139 5-cyano-pyridin-3-yl 4-isopropyloxy-phenyl a₁-L₁ pyrrolidin-2-yl methyl H 2S 140 pyrimidin-5-yl 4-isopropyloxy-phenyl a₁-L₁ pyrrolidin-2-yl methyl H 2S 141 pyridin-3-yl 4-isopropyloxy-phenyl a₁-L₁ pyrrolidin-2-yl methyl H 2S 142 3-cyano-5-fluoro- 4-methoxy-phenyl a₁-L₁ pyrrolidin-2-yl methyl H 2S phenyl 143 5-cyano-pyridin-3-yl 4-hydroxymethyl-phenyl a₁-L₁ pyrrolidin-2-yl methyl H 2S 144 pyrimidin-5-yl 4-hydroxymethyl-phenyl a₁-L₁ pyrrolidin-2-yl methyl H 2S 145 pyridin-3-yl 4-hydroxymethyl-phenyl a₁-L₁ pyrrolidin-2-yl methyl H 2S 146 5-cyano-pyridin-3-yl 4-fluoro-phenyl a₁-L₁ pyrrolidin-2-yl methyl H 2S 147 5-cyano-pyridin-3-yl 4-methyl-phenyl a₁-L₁ pyrrolidin-2-yl methyl H 2S 148 pyrimidin-5-yl 4-methyl-phenyl a₁-L₁ pyrrolidin-2-yl methyl H 2S 149 pyridin-3-yl 4-methyl-phenyl a₁-L₁ pyrrolidin-2-yl methyl H 2S 150 5-cyano-pyridin-3-yl 4-methylthio-phenyl a₁-L₁ pyrrolidin-2-yl methyl H 2S 151 pyrimidin-5-yl 4-methylthio-phenyl a₁-L₁ pyrrolidin-2-yl methyl H 2S 152 pyridin-3-yl 4-methylthio-phenyl a₁-L₁ pyrrolidin-2-yl methyl H 2S 153 5-cyano-pyridin-3-yl 4-(methoxymethyl)-phenyl a₁-L₁ pyrrolidin-2-yl methyl H 2S 154 pyrimidin-5-yl 4-(methoxymethyl)-phenyl a₁-L₁ pyrrolidin-2-yl methyl H 2S 155 pyridin-3-yl 4-(methoxymethyl)-phenyl a₁-L₁ pyrrolidin-2-yl methyl H 2S 156 pyrimidin-5-yl 4-hydroxy-phenyl a₁-L₁ pyrrolidin-2-yl methyl H 2S 157 pyridin-3-yl 3-diethylaminocarbonyl- a₁-L₁ pyrrolidin-2-yl methyl H 2S phenyl 158 pyridin-3-yl 4-pyrrolidin-1-ylcarbonyl- a₁-L₁ pyrrolidin-2-yl methyl H 2S phenyl 159 pyridin-3-yl 4-carboxy-phenyl a₁-L₁ pyrrolidin-2-yl methyl H 2S 160 pyridin-3-yl 4-piperidin-1-ylcarbonyl- a₁-L₁ pyrrolidin-2-yl methyl H 2S phenyl 161 pyridin-3-yl 4-(morpholin-4- a₁-L₁ pyrrolidin-2-yl methyl H 2S ylcarbonyl)-phenyl 162 pyridin-3-yl 4-(4-methyl-piperazin- a₁-L₁ pyrrolidin-2-yl methyl H 2S 1-ylcarbonyl)-phenyl 163 pyridin-3-yl 3-carboxy-phenyl a₁-L₁ pyrrolidin-2-yl methyl H 2S 164 5-fluoro-pyridin-3-yl 3-carboxy-phenyl a₁-L₁ pyrrolidin-2-yl methyl H 2S 165 5-fluoro-pyridin-3-yl 4-carboxy-phenyl a₁-L₁ pyrrolidin-2-yl methyl H 2S 166 pyridin-3-yl 3-(pyrrolidin-1- a₁-L₁ pyrrolidin-2-yl methyl H 2S ylcarbonyl)-phenyl 167 pyridin-3-yl 3-(piperidin-1- a₁-L₁ pyrrolidin-2-yl methyl H 2S ylcarbonyl)-phenyl 168 pyridin-3-yl 3-(morpholin-4- a₁-L₁ pyrrolidin-2-yl methyl H 2S ylcarbonyl)-phenyl 169 pyridin-3-yl 3-(4-methyl-piperazin-1- a₁-L₁ pyrrolidin-2-yl methyl H 2S ylcarbonyl)-phenyl 170 5-fluoro-pyridin-3-yl 3-diethylaminocarbonyl- a₁-L₁ pyrrolidin-2-yl methyl H 2S phenyl 171 5-fluoro-pyridin-3-yl 3-(pyrrolidin-1- a₁-L₁ pyrrolidin-2-yl methyl H 2S ylcarbonyl)-phenyl 172 5-fluoro-pyridin-3-yl 3-(piperidin-1- a₁-L₁ pyrrolidin-2-yl methyl H 2S ylcarbonyl)-phenyl 173 5-fluoro-pyridin-3-yl 3-(morpholin-4- a₁-L₁ pyrrolidin-2-yl methyl H 2S ylcarbonyl)-phenyl 174 5-fluoro-pyridin-3-yl 3-(4-methyl-piperazin-1- a₁-L₁ pyrrolidin-2-yl methyl H 2S ylcarbonyl)-phenyl 175 pyridin-3-yl 4-diethylaminocarbonyl- a₁-L₁ pyrrolidin-2-yl methyl H 2S phenyl 176 5-fluoro-pyridin-3-yl 4-(pyrrolidin-1- a₁-L₁ pyrrolidin-2-yl methyl H 2S ylcarbonyl)-phenyl 177 pyridin-3-yl 4- a₁-L₁ pyrrolidin-2-yl methyl H 2S benzyloxycarbonylamino- phenyl 178 5-fluoro-pyridin-3-yl 4-methyl-phenyl a₁-L₁ pyrrolidin-2-yl methyl H 2S 179 5-cyano-pyridin-3-yl 4-ethyl-phenyl a₁-L₁ pyrrolidin-2-yl methyl H 2S 180 5-chloro-pyridin-3-yl 4-ethyl-phenyl a₁-L₁ pyrrolidin-2-yl methyl H 2S 181 pyrimidin-5-yl 4-methoxy-phenyl a₁-L₁ pyrrolidin-2-yl methyl —C(O)Me 2S 182 5-fluoro-pyridin-3-yl 4-ethyl-phenyl a₁-L₁ pyrrolidin-2-yl methyl H 2S 183 5-cyano-pyridin-3-yl 3-fluoro-4-methyl-phenyl a₁-L₁ pyrrolidin-2-yl methyl H 2S 184 pyridin-3-yl 4-ethyl-phenyl a₁-L₁ pyrrolidin-2-yl methyl H 2S 185 5-fluoro-pyridin-3-yl 3-fluoro-4-methyl-phenyl a₁-L₁ pyrrolidin-2-yl methyl H 2S 186 5-chloro-pyridin-3-yl 3-fluoro-4-methyl-phenyl a₁-L₁ pyrrolidin-2-yl methyl H 2S 187 pyridin-3-yl 3-fluoro-4-methyl-phenyl a₁-L₁ pyrrolidin-2-yl methyl H 2S 188 pyridin-3-yl 3-benzyloxycarbonylamino- a₁-L₁ pyrrolidin-2-yl methyl H 2S phenyl 189 5-cyano-pyridin-3-yl 2,3-difluoro-4-methyl- a₁-L₁ pyrrolidin-2-yl methyl H 2S phenyl 190 5-chloro-pyridin-3-yl 2,3-difluoro-4-methyl- a₁-L₁ pyrrolidin-2-yl methyl H 2S phenyl 191 5-fluoro-pyridin-3-yl 2,3-difluoro-4-methyl- a₁-L₁ pyrrolidin-2-yl methyl H 2S phenyl 192 pyridin-3-yl 2,3-difluoro-4-methyl- a₁-L₁ pyrrolidin-2-yl methyl H 2S phenyl 193 5-fluoro-pyridin-3-yl 4-methoxy-phenyl a₁-L₁ 4-fluoro- methyl H 2S,4R pyrrolidin-2-yl 194 5-chloro-pyridin-3-yl 4-methoxy- a₁-L₁ 4-fluoro- methyl H 2S,4R phenyl pyrrolidin-2-yl 195 5-cyano-pyridin-3-yl 4-ethyl-phenyl a₁-L₁ 4-fluoro- methyl H 2S,4R pyrrolidin-2-yl 196 pyridin-3-yl 4-methoxy-phenyl a₁-L₁ 4-fluoro- methyl H 2S,4R pyrrolidin-2-yl 197 5-fluoro-pyridin-3-yl 4- a₁-L₁ pyrrolidin-2-yl methyl H 2S benzyloxycarbonylamino- phenyl 198 5-fluoro-pyridin-3-yl 4-amino-phenyl a₁-L₁ pyrrolidin-2-yl methyl H 2S 199 5-cyano-pyridin-3-yl 4-methoxy-phenyl a₁-L₁ piperidin-3-yl absent H 3S 200 5-cyano-pyridin-3-yl 3-methyl-phenyl a₁-L₁ pyrrolidin-2-yl methyl H 2S 201 5-chloro-pyridin-3-yl 3-methyl-phenyl a₁-L₁ pyrrolidin-2-yl methyl H 2S 202 5-fluoro-pyridin-3-yl 3-methyl-phenyl a₁-L₁ pyrrolidin-2-yl methyl H 2S 203 pyridin-3-yl 3-methyl-phenyl a₁-L₁ pyrrolidin-2-yl methyl H 2S 204 5-cyano-pyridin-3-yl 3-methyl-4-methoxy-phenyl a₁-L₁ pyrrolidin-2-yl methyl H 2S 205 5-fluoro-pyridin-3-yl 3-methyl-4-methoxy-phenyl a₁-L₁ pyrrolidin-2-yl methyl H 2S 206 5-cyano-pyridin-3-yl 4-fluoromethyl-phenyl a₁-L₁ pyrrolidin-2-yl methyl H 2S 207 5-cyano-pyridin-3-yl 4-methoxy-phenyl a₁-L₁ piperidin-3-yl absent H 3S 208 5-cyano-pyridin-3-yl 4-methoxy-phenyl a₁-L₁ piperidin-4-yl absent H 209 pyridin-3-yl 4-(pyridin-3-ylmethyl)- a₁-L₁ pyrrolidin-2-yl methyl H 2S phenyl 210 5-chloro-pyridin-3-yl 3-methyl-4-methoxy-phenyl a₁-L₁ pyrrolidin-2-yl methyl H 2S 211 pyridin-3-yl 3-methyl-4-methoxy-phenyl a₁-L₁ pyrrolidin-2-yl methyl H 2S 212 5-fluoro-pyridin-3-yl 4-(methylcarbonylamino)- a₁-L₁ pyrrolidin-2-yl methyl H 2S phenyl 213 5-fluoro-pyridin-3-yl 4-methanesulfonylamino- a₁-L₁ pyrrolidin-2-yl methyl H 2S phenyl 214 pyridin-3-yl 4-methanesulfonylamino- a₁-L₁ pyrrolidin-2-yl methyl H 2S phenyl 215 5-cyano-pyridin-3-yl 4-methoxy-phenyl a₁-L₁ azetidin-3-yl methyl H 216 pyridin-3-yl 4-formamido-phenyl a₁-L₁ pyrrolidin-2-yl methyl H 2S 217 pyridin-3-yl 4-fluoromethyl-phenyl a₁-L₁ pyrrolidin-2-yl methyl H 2S 218 5-cyano-pyridin-3-yl 3-methyl-4-fluoro-phenyl a₁-L₁ pyrrolidin-2-yl methyl H 2S 219 5-fluoro-pyridin-3-yl 3-methyl-4-fluoro-phenyl a₁-L₁ pyrrolidin-2-yl methyl H 2S 220 5-cyano-pyridin-3-yl 4-trifluoromethyl-phenyl a₁-L₁ pyrrolidin-2-yl methyl H 2S 221 5-fluoro-pyridin-3-yl 4-trifluoromethyl-phenyl a₁-L₁ pyrrolidin-2-yl methyl H 2S 222 5-fluoro-pyridin-3-yl 4-methanesulfonyl-phenyl a₁-L₁ pyrrolidin-2-yl methyl H 2S 223 5-fluoro-pyridin-3-yl 4-formamido-phenyl a₁-L₁ pyrrolidin-2-yl methyl H 2S 224 pyridin-3-yl 4-methoxy-phenyl a₁-L₁ pyrrolidin-3-yl absent H 3R 225 pyridin-3-yl 4-methoxy-phenyl a₁-L₁ piperidin-2-yl methyl H 2S 226 pyridin-3-yl 4-methoxy-phenyl a₁-L₁ azetidin-3-yl absent H 227 5-chloro-pyridin-3-yl 2-methyl-phenyl a₁-L₁ pyrrolidin-2-yl methyl H 2S 228 5-cyano-pyridin-3-yl 3-methylcarbonyloxy- a₁-L₁ pyrrolidin-2-yl methyl H 2S phenyl 229 5-chloro-pyridin-3-yl 2-chloro-phenyl a₁-L₁ pyrrolidin-2-yl methyl H 2S 230 5-cyano-pyridin-3-yl 2-chloro-phenyl a₁-L₁ pyrrolidin-2-yl methyl H 2S 231 5-cyano-pyridin-3-yl 3-hydroxy-phenyl a₁-L₁ pyrrolidin-2-yl methyl H 2S 232 5-methoxy-pyridin-3-yl 2-chloro-phenyl a₁-L₁ pyrrolidin-2-yl methyl H 2S 233 5-methylthio-pyridin- 2-chloro-phenyl a₁-L₁ pyrrolidin-2-yl methyl H 2S 3-y 234 5-methylthio-pyridin- 4-methoxy-phenyl a₁-L₁ 4-fluoro- methyl H 2S,4R 3-y pyrrolidin-2-yl 235 5-methoxy-pyridin-3-yl 4-methoxy-phenyl a₁-L₁ 4-fluoro- methyl H 2S,4R pyrrolidin-2-yl 236 pyridin-3-yl 4-methoxy-phenyl a₁-L₁ piperidin-3-yl absent H 3S 237 pyridin-3-yl 4-methoxy-phenyl a₁-L₁ pyrrolidin-3-yl absent H 3S 238 5-methyl-pyridin-3-yl 4-methoxy-phenyl a₁-L₁ 4-fluoro- methyl H 2S,4R pyrrolidin-2-yl 239 5-methyl-pyridin-3-yl 4-methoxy-phenyl a₁-L₁ 4-fluoro- methyl H 2S,4S pyrrolidin-2-yl 240 5-methoxy-pyridin- 4-methoxy-phenyl a₁-L₁ 4-fluoro- methyl H 2S,4S 3-yl pyrrolidin-2-yl 241 5-methylthio-pyridin- 4-(2-methoxy-ethoxy)- a₁-L₁ pyrrolidin-2-yl methyl H 2S 3-yl phenyl 242 5-methyl-pyridin-3-yl 4-(2-methoxy-ethoxy)- a₁-L₁ pyrrolidin-2-yl methyl H 2S phenyl 243 5-methoxy-pyridin-3-yl 4-(2-methoxy-ethoxy)- a₁-L₁ pyrrolidin-2-yl methyl H 2S phenyl 244 pyridin-3-yl 4-(2-methoxy-ethoxy)- a₁-L₁ pyrrolidin-2-yl methyl H 2S phenyl 245 5-methoxy-pyridin-3-yl 4-methoxy-phenyl a₁-L₁ piperidin-3-yl absent H 3S 246 5-methoxy-pyridin-3-yl 4-methoxy-phenyl a₁-L₁ piperidin-3-yl absent H 3R 247 5-methoxy-pyridin-3-yl 4-methoxy-phenyl a₁-L₁ piperidin-3-yl absent H 3S 248 5-methylthio-pyridin- 3-methylcarbonyloxy- a₁-L₁ pyrrolidin-2-yl methyl H 2S 3-yl phenyl 249 5-methoxy-pyridin-3-yl 3-hydroxy-phenyl a₁-L₁ pyrrolidin-2-yl methyl H 2S 250 5-methoxy-pyridin-3-yl 3-methylcarbonyloxy- a₁-L₁ pyrrolidin-2-yl methyl H 2S phenyl 251 5-methyl-pyridin-3-yl 3-methylcarbonyloxy- a₁-L₁ pyrrolidin-2-yl methyl H 2S phenyl 252 5-methylthio-pyridin- 4-methoxy-phenyl a₁-L₁ piperidin-3-yl absent H 3S 3-yl 253 5-methyl-pyridin-3-yl 4-methoxyphenyl a₁-L₁ pyrrolidin-2-yl methyl H 2S 254 5-methylthiopyridin- 4-methoxyphenyl a₁-L₁ piperidin-3-yl absent H 3R 3-yl 255 5-methylthiopyridin- 4-methoxyphenyl a₁-L₁ pyrrolidin-3-yl absent H 3S 3-yl 256 5-methoxypyridin-3-yl 4-methoxyphenyl a₁-L₁ pyrrolidin-3-yl absent H 3S 257 5-methyl-pyridin-3-yl 4-methoxyphenyl a₁-L₁ pyrrolidin-3-yl absent H 3S 258 5-methyl-pyridin-3-yl 4-methoxyphenyl a₁-L₁ piperidin-3-yl absent H 3R 259 5-methyl-pyridin-3-yl 4-methoxyphenyl a₁-L₁ piperidin-3-yl absent H 3S 260 5-methyl-pyridin-3-yl 4-fluoromethoxyphenyl a₁-L₁ pyrrolidin-2-yl methyl H 2S 261 pyridin-3-yl 4-methoxyphenyl a₁-L₁ piperidin-3-yl absent H 3R 262 6-fluoro-5- 4-methoxyphenyl a₁-L₁ pyrrolidin-2-yl methyl H 2S methylpyridin-3-yl 263 2,5-dimethyl-pyridin- 4-methoxyphenyl a1-L₁ pyrrolidin-2-yl methyl H 2S 3-yl 264 6′-chloro-3,5′- 4-methoxyphenyl a₁-L₁ pyrrolidin-2-yl methyl H 2S dimethyl-[2,3′] bipyridinyl-5-yl 265 6-chloro-4-methyl 4-methoxyphenyl a₁-L₁ pyrrolidin-2-yl methyl H 2S pyridin-3-yl 266 6-chloro-5-methyl- 4-methoxyphenyl a₁-L₁ pyrrolidin-2-yl methyl H 2S pyridin-3-yl 267 pyridin-3-yl 4-methoxyphenyl a₁-L₁ piperidin-2-yl methyl H 2R 268 2-chloro-5- 4-methoxyphenyl a₁-L₁ pyrrolidin-2-yl methyl H 2S methylpyridin-3-yl 269 5-hydroxymethyl- 4-methoxyphenyl a₁-L₁ pyrrolidin-2-yl methyl H 2S pyridin-3-yl 270 pyridin-3-yl 4-methoxyphenyl a₁-L₁ 4-hydroxy- methyl H trans pyrrolidin-2-yl 2S,4R 271 pyridin-3-yl 4-methoxyphenyl a1-L₁ 4-hydroxy methyl H cis pyrrolidin-2-yl 2R,4R 272 pyridin-3-yl 4-methoxyphenyl a₁-L₁ 4-hydroxy- methyl H cis pyrrolidin-2-yl 2S,4S 273 5-methoxypyridin-3-yl 4-methoxyphenyl a₁-L₁ 4-hydroxy- methyl H trans pyrrolidin-2-yl 2S,4R 274 5-methoxypyridin-3-yl 4-methoxyphenyl a₁-L₁ 4-hydroxy- methyl H cis pyrrolidin-2-yl 2R,4R 275 5-cyano-pyridin-3-yl 4-methoxy-phenyl a₂-L₂ morpholin-2-yl methyl H racemic 276 5-fluoro-pyridin-3-yl 4-methoxy-phenyl a₂-L₂ morpholin-2-yl methyl H 277 pyrimidin-5-yl 4-methoxy-phenyl a₂-L₂ morpholin-2-yl methyl H 278 pyrimidin-5-yl 4-methoxy-phenyl a₂-L₂ morpholin-3-yl methyl H racemic 279 5-cyano-pyridin-3-yl 4-methoxy-phenyl a₂-L₂ morpholin-3-yl methyl H racemic 280 5-cyano-pyridin-3-yl 4-methoxy-phenyl a₂-L₂ morpholin-3-yl methyl H 3S 281 5-fluoro-pyridin-3-yl 4-methoxy-phenyl a₂-L₂ morpholin-3-yl methyl H 3S 282 pyridin-3-yl 4-methoxy-phenyl a₂-L₂ morpholin-3-yl methyl H 3S 283 5-cyano-pyridin-3-yl 4-methoxy-phenyl a₃-L₃ imidazol-2-yl methylene H 284 5-cyano-pyridin-3-yl 4-methoxy-phenyl a₃-L₃ 3H-imidazol-4-yl methylene H 285 5-cyano-pyridin-3-yl 4-methoxy-phenyl a₃-L₃ 5-methyl-3H- methyl H 0 imidazol-4-yl 286 5-cyano-pyridin-3-yl 4-methoxy-phenyl a₃-L₃ 3-methyl-3H- methyl H 0 imidazol-4-yl 287 5-cyano-pyridin-3-yl 4-methoxy-phenyl a₃-L₃ 2-ethyl-5- methyl H methyl-3H- imidazol-4-yl 288 pyridin-3-yl 4-methoxy-phenyl a₃-L₃ 3H-imidazol-4-yl methyl H 289 5-methylthio-pyridin- 4-methoxy-phenyl a₃-L₃ 3H-imidazol-4-yl methyl H 3-yl 290 5-methoxy-pyridin-3-yl 4-methoxy-phenyl a₃-L₃ 3H-imidazol-4-yl methyl H 291 5-methyl-pyridin-3-yl 4-methoxy-phenyl a₃-L₃ 3H-imidazol-4-yl methyl H 292 5-cyano-pyridin-3-yl 4-methoxy-phenyl a₄-L₄ 2-amino propyl H 2S 293 5-cyano-pyridin-3-yl 4-methoxy-phenyl a₄-L₄ 2-amino ethyl H 294 5-cyano-pyridin-3-yl 4-methoxy-phenyl a₄-L₄ 2-amino 4-methyl- H 2S pentyl 295 pyrimidin-5-yl 4-methoxy-phenyl a₄-L₄ 2-amino 4-methyl- H 2S pentyl 296 5-methyl-pyridin-3-yl 4-methoxyphenyl a₄-L₄ 2-amino ethyl H 297 pyridin-3-yl 4-methoxyphenyl a₄-L₄ 2-methylamino ethyl H 298 5-cyano-pyridin-3-yl 4-methoxy-phenyl a₅-L₅ 4-aminocyclohexyl absent H cis/trans mixture 299 5-cyano-pyridin-3-yl 4-methoxy-phenyl a₅-L₅ 2-aminocyclohexyl methyl H 2S,1R 300 pyrimidin-5-yl 4-methoxy-phenyl a₅-L₅ 2-aminocyclohexyl methyl H 2S,1R 301 5-cyano-pyridin-3-yl 4-methoxy-phenyl a₅-L₅ 3-aminocyclobutyl methyl H trans 302 pyrimidin-5-yl 4-methoxy-phenyl a₅-L₅ 3-aminocyclobutyl methyl H trans 303 5-cyano-pyridin-3-yl 4-methoxy-phenyl a₅-L₅ 3-aminocyclobutyl absent H cis/trans mixture 304 pyrimidin-5-yl 4-methoxy-phenyl a₅-L₅ 3-aminocyclobutyl absent H cis/trans mixture 305 pyridin-3-yl 4-methoxy-phenyl a₅-L₅ 4-aminocyclohexyl absent H cis 306 pyridin-3-yl 4-methoxy-phenyl a₅-L₅ 3-aminocyclohexyl absent H Racemic, mixture of cis/trans 307 pyridin-3-yl 4-methoxy-phenyl a₅-L₅ 3-aminocyclohexyl absent H 1RS,3SR (racemic cis) 308 pyridin-3-yl 4-methoxy-phenyl a₅-L₅ 2-aminocyclohexyl absent H 1RS,2SR (racemic single stereoisomer, unknown cis/trans) 309 5-methoxy-pyridin-3-yl 4-methoxy-phenyl a₅-L₅ 3-aminocyclohexyl absent H Racemic, mixture of cis/trans 310 5-methylthiopyridin-3- 4-methoxyphenyl a₅-L₅ 3-aminocyclohexyl absent H Racemic, yl mixture of cis/trans 311 5-methoxypyridin-3-yl 4-methoxyphenyl a₅-L₅ 3-aminocyclohexyl absent H cis 1R,3S 312 5-methoxypyridin-3-yl 4-methoxyphenyl a₅-L₅ 3-aminocyclohexyl absent H cis 1S,3R 313 5-methoxypyridin-3-yl 4-methoxyphenyl a₅-L₅ 3-aminocyclohexyl absent H trans, one enant. Absolute unknown 314 5-methoxypyridin-3-yl 4-methoxyphenyl a₅-L₅ 3-aminocyclohexyl absent H trans, one enant., absolute unknown 315 5-methyl-pyridin-3-yl 4-methoxyphenyl a₅-L₅ 3-aminocyclohexyl absent H Racemic, mixture of cis/trans 316 5-methylthiopyridin-3- 4-methoxyphenyl a₅-L₅ 3-aminocyclohexyl absent H cis yl 1S,3R 317 5-methylthiopyridin-3- 4-methoxyphenyl a₅-L₅ 3-aminocyclohexyl absent H cis yl 1R,3S 318 5-methylthiopyridin-3- 4-methoxyphenyl a₅-L₅ 3-aminocyclohexyl absent H trans, yl one enant., absolute unknown 319 5-methylthiopyridin-3- 4-methoxyphenyl a₅-L₅ 3-aminocyclohexyl absent H trans, yl one enant., absolute unknown 321 pyridin-3-yl 4-methoxyphenyl a₅-L₅ 3-aminocyclohexyl absent H cis 1S,3R 322 pyridin-3-yl 4-methoxyphenyl a₅-L₅ 3-aminocyclohexyl absent H cis 1R,3S 323 pyridin-3-yl 4-methoxyphenyl a₅-L₅ 3-aminocyclohexyl absent H trans, one enant., absolute unknown Compounds 320, and 324 through 361 of Formula (I), in the table below were synthesized using the procedures described above.

Formula (I)

Cpd A—L— and R_(a) are Stereo No R₁ R₂ taken to form chem 320 pyridin-3-yl 4- piperazin-1-yl cyclopropyl- phenyl 324 phenyl 4-methoxy- piperazin-1-yl phenyl 325 5-cyano- 4-methoxy- piperazin-1-yl pyridin-3-yl phenyl 326 5-cyano- 4-methoxy- 3-amino 3R pyridin-3-yl phenyl pyrrolidin-1-yl 327 pyridin-3-yl 4-methoxy- piperazin-1-yl phenyl 328 5-cyano- 4-methoxy- 3-amino 3S pyridin-3-yl phenyl pyrrolidin-1-yl 329 5-cyano- 4-methoxy- 3-amino 3S pyridin-3-yl phenyl piperidin-1-yl 330 5-cyano- 4-methoxy- 3-amino 3R pyridin-3-yl phenyl piperidin-1-yl 331 5-cyano- 4-methoxy- 3-aminomethyl pyridin-3-yl phenyl azetidin-1-yl 332 5-cyano- 4-methoxy- 2-aminomethyl 2R pyridin-3-yl phenyl pyrrolidin-1-yl 333 5-cyano- 4-methoxy- 4-amino pyridin-3-yl phenyl piperidin-1-yl 334 5-cyano- 4-methoxy- 2-aminomethyl 2R pyridin-3-yl phenyl pyrrolidin-1-yl 335 5-cyano- 4-methoxy- 3-oxopiperazin-1-yl pyridin-3-yl phenyl 336 pyridin-3-yl 4-methoxy- [1,4]diazepan-1-yl phenyl 337 5-cyano- 4-methoxy- 2-oxopiperazin-1-yl pyridin-3-yl phenyl 338 5-cyano- 4-methoxy- 3,6-diaza- pyridin-3-yl phenyl bicyclo[3.1.1] hept-3-ylamino 339 pyridin-3-yl 4-methoxy- 3-amino 3R phenyl pyrrolidin-1-yl 340 pyridin-3-yl 4-methoxy- 3-amino-azetidin-1-yl phenyl 341 5-methylthio- 4-methoxy- piperazin-1-yl pyridin-3-y phenyl 342 5-methoxy- 4-methoxy- piperazin-1-yl pyridin-3-yl phenyl 343 5-cyano- 4-methoxy- 3-methyl- racemic pyridin-3-yl phenyl piperazin-1-yl 344 5-cyano- 4-methoxy- 2-methyl- 2R pyridin-3-yl phenyl piperazin-1-yl 345 5-cyano- 4-methoxy- 2-methyl- 2S pyridin-3-yl phenyl piperazin-1-yl 346 5-methoxy- 4-methoxy- [1,4]-diazepan-1-yl pyridin-3-yl phenyl 347 5-methylthio 4-methoxy [1,4]-diazepan-1-yl pyridin-3-yl phenyl 348 5-methylthio 4-methoxy 3-amino-pyrrolidin-1- 3R pyridin-3-yl phenyl yl 349 5-methoxy 4-methoxy 3-amino- 3R pyridin-3-yl phenyl pyrrolidin-1-yl 350 5-methylthio 4-methoxy 3,3-dimethyl- pyridin-3-yl phenyl piperazin-1-yl 351 5-methyl- 4-methoxy piperazin-1-yl pyridin-3-yl phenyl 352 5-methyl- 4-methoxy 3-amino- 3R pyridin-3-yl phenyl pyrrolidin-1-yl 353 pyridin-3-yl 4-methoxy 4-methyl- phenyl piperazin-1-yl 354 pyridin-3-yl 4-methoxy 2-methyl- 2S phenyl piperazin-1-yl 355 pyridin-3-yl 4-methoxy 3,3-dimethyl- phenyl piperazin-1-yl 356 pyridin-3-yl 4-methoxy 3-methyl- 3S phenyl piperazin-1-yl 357 pyridin-3-yl 4-methoxy 3-methyl- 3R phenyl piperazin-1-yl 358 5-methyl- 4-methoxy [1,4]diazepan-1-yl pyridin-3-yl phenyl 359 pyridin-3-yl 4-methoxy 3,5-dimethyl- cis phenyl piperazin-1-yl 360 5-methoxy 4-methoxy 2-ethyl- 2S pyridin-3-yl phenyl piperazin-1-yl 361 5-methoxy 4-methoxy 3-ethyl- 3R pyridin-3-yl phenyl piperazin-1-yl

Biological Examples In Vitro Assays Example 1 NG108-15, 24-Well Delta Opioid Receptor Binding Assay

Methods: NG108-15 cell membranes were purchased from Applied Cell Sciences (Rockville, Md.). 5 mg/mL of membrane protein was suspended in 10 mM TRIS-HCl pH 7.2, 2 mM EDTA, 10% sucrose. With several brief pulses from a Polytron homogenizer, each vial was homogenized in 5 mls of 50 mM Tris Buffer, pH 7.4. The homogenate was diluted in 50 mM Tris Buffer containing 5 mM MgCl₂ to 330 ug/ml in the working solution for a final concentration of 133 ug/well. This particulate preparation was used for the 24-well delta opioid binding assay.

Following incubation with the delta selective peptide ligand ˜0.2 nM [³H]Naltrindole at 25° C. for 2.5 h in a 24-well plate with total volume of 1 mL, the plate contents were filtered through a UniFilter24, GF/B. This plate was presoaked in 0.3% PEI and filtered through a 24-well Harvester. The UniFilter24 was rinsed three times with 2 mL of 10 mM HEPES (pH 7.4), and dried in an oven at 37° C. for 1.5 hours. To each well, was added 150 uL of Scint0 (PerkinElmer, Cat#6013611). The plates were then read on a TopCount.

Analysis: The data from the scintillation counter were used to calculate either the % inhibition compared to control binding (when only a single concentration of test compound was evaluated) or a K_(i) value (when a range of concentrations was tested). Non-specific binding (N.S.-1 mM Naloxone) is used as the negative control, while the Total Binding (T.B.-Membrane and ligand only) is used as the positive control. If one concentration is screened, the % inhibition is calculated as (cpms of total binding minus cpms of compound) divided by (cpms of T.B.minus cpms of N.S). The triplicate % Inhibitions are averaged and reported. If multiple concentrations are generated, the values are analyzed using the one-site binding non-linear regression program in Prism to determine Ki values. The bottom and top values are globally shared. The triplicate K is are then averaged and reported.

The data obtained are shown in Table 2, below.

Example 2 Rat Brain Delta Opioid Receptor Binding Assay

Procedure: Male, Wistar rats (150-250 g, VAF, Charles River, Kingston, N.Y.) were killed by CO₂, and their brains were removed and placed immediately in ice cold Tris HCl buffer (50 mM, pH 7.4). The forebrains were separated from the remainder of the brain by a coronal transection, beginning dorsally at the colliculi and passing ventrally through the midbrain-pontine junction. After dissection, the forebrains were homogenized in Tris buffer in a Teflon®-glass homogenizer. The homogenate was diluted to a concentration of 1 g of forebrain tissue per 80 mL Tris and centrifuged at 39,000×g for 10 min. The pellet was resuspended in the same volume of Tris buffer containing 5 mM MgCl₂ with several brief pulses from a Polytron homogenizer. This particulate preparation was used for the delta opioid binding assays. Following incubation with the delta selective peptide ligand ˜4 nM [³H]DPDPE or 0.25 nM [³H]naltrindole at 25° C. for 2.5 h in a 96-well plate with total volume of 1 mL, the plate contents were filtered through Wallac filtermat B sheets on a Tomtec 96-well harvester. The filters were rinsed three times with 2 mL of 10 mM HEPES (pH 7.4), and dried in a 650 W microwave oven for 1.75 min twice. To each sample area 2×50 μL of Betaplate Scint scintillation fluid (LKB) was added and the radioactivity was quantified on a LKB (Wallac) 1205 BetaPlate liquid scintillation counter.

Analysis: The data from the scintillation counter were used to calculate either the % inhibition compared to control binding (when only a single concentration of test compound was evaluated) or a K_(i) value (when a range of concentrations was tested). Percent inhibition was calculated as: [(total dpm-test compound dpm)/(total dpm-nonspecific dpm)]*100. Kd and Ki values were calculated using GraphPad PRISM data analysis program. The data obtained are shown in Table 2, below.

Example 3 Rat Brain Mu Opioid Receptor Binding Assay

Procedure: Male, Wistar rats (150-250 g, VAF, Charles River, Kingston, N.Y.) were killed by CO₂, and their brains were removed and placed immediately in ice cold Tris HCl buffer (50 mM, pH 7.4). The forebrains were separated from the remainder of the brain by a coronal transection, beginning dorsally at the colliculi and passing ventrally through the midbrain-pontine junction. After dissection, the forebrains were homogenized in Tris buffer in a Teflon®-glass homogenizer. The homogenate was diluted to a concentration of 1 g of forebrain tissue per 80 mL Tris and centrifuged at 39,000×g for 10 min. The pellet was resuspended in the same volume of Tris buffer containing 5 mM MgCl₂ with several brief pulses from a Polytron homogenizer. This particulate preparation was used for the mu opioid binding assays. Following incubation with the mu selective peptide ligand, ˜0.8 nM [³H]DAMGO, at 25° C. for 2.5 h in a 96-well plate with total assay volume of 1 mL, the plate contents were filtered through Wallac filtermat B sheets on a Tomtec 96-well harvester. The filters were rinsed three times with 2 mL of 10 mM HEPES (pH 7.4), and dried in a 650 W microwave oven for 1.75 min twice. To each sample area 2×40 μL of Betaplate Scint scintillation fluid (LKB) was added and the radioactivity was quantifed on a LKB (Wallac) 1205 BetaPlate liquid scintillation counter.

Analysis: The data from the scintillation counter was used to calculate either the % inhibition compared to control binding (when only a single concentration of test compound was evaluated) or a K_(i) value (when a range of concentrations was tested). Percent inhibition was calculated as: [(total dpm-test compound dpm)/(total dpm-nonspecific dpm)]*100. Kd and Ki values were calculated using GraphPad PRISM data analysis program. The data obtained are shown in Table 2, below.

TABLE 2 Delta and Mu Opioid Receptor Binding Data δ-binding δ-binding δ-binding NG108 cell (DPDPE (Naltrindole Cpd membrane ligand) ligand) μ-binding No. K_(i) (μM) K_(i) (μM) K_(i) (μM) K_(i) (μM) 1 0.363 3.228 2 0.020 0.033 3.387, 3.139 3 0.142 2.345 4 2.217 >10 5 0.157 >10 6 0.116 9.007 7 0.013 2.169 8 0.00619 0.0428 9 0.001 2.968 10 0.034 2.000 11 0.005 3.083 12 0.018 4.516 13 0.002 5.568 14 0.001 1.731 15 0.0001 0.416 16 0.014 1.317 17 0.030 3.081 18 0.172 2.237 19 0.201 8.084 20 0.00493 0.146 21 0.201 2.387 22 0.000909 1.100 23 0.00125 0.214 24 0.001 1.064 25 0.000308 0.616 26 0.008 4.049 27 2.569 15.549 28 0.00610 0.295 29 0.086 2.663 30 0.003 1.087 31 0.031 0.837 32 0.0126 0.0641 33 0.029 0.029 34 0.015 0.015 35 0.184 0.184 36 0.003 4.769 37 0.010 >10 38 0.001 4.906 39 0.067 8.991 40 0.093 7.642 41 0.041 1.529 42 0.016 1.230 43 0.004 0.523 44 0.004 2.693 45 0.011 0.812 46 0.027 3.550 47 0.006 1.126 48 0.024 0.862 49 0.103 3.563 50 0.055 0.597 51 0.022 1.026 52 0.0004 0.539 53 0.0002 0.591 54 0.000188 0.00033 0.2172 55 0.021 2.046 56 0.015 1.944 57 0.011 0.113 58 0.004 0.640 59 0.00154 0.000954 1.610 60 0.014 1.523 61 0.259 3.988 62 0.544 1.915 63 0.037 0.633 64 0.008 0.466 65 0.003 0.555 66 0.010 0.390 67 0.001 1.561 68 0.002 0.465 69 0.000139 0.0041 0.196 70 0.047 2.253 72 0.002 0.732 73 0.003 1.102 74 0.026 1.062 75 0.036 5.117 76 0.111 0.333 77 0.154 0.313 78 0.075 1.878 79 0.095 >10 80 0.002 0.106 81 0.355 0.569 82 0.028 1.050 83 0.014 0.673 84 0.016 0.338 85 0.002 >10 86 0.002 1.176 87 0.072 88 0.014 89 0.010 90 0.009 91 0.022 92 0.035 93 0.008 0.554 94 0.143 95 0.011 96 0.035 97 0.039 98 0.003 0.102 99 0.059 100 0.033 101 0.007 0.058 102 0.003 103 0.011 104 0.008 0.190 105 0.003 0.421 106 0.006 0.042 107 0.001 0.039 108 0.107 109 0.001 0.522 110 0.033 1.071 111 0.009 112 0.006 113 0.045 1.433 114 0.008 115 0.052 117 0.157 118 0.155 119 4.018 120 0.104 121 0.020 0.379 122 0.122 123 0.0004 124 0.0003 0.126 125 0.078 126 0.565 127 0.224 128 0.0004 129 0.0003 130 0.002 131 0.0002 132 0.0004 0.061 133 0.0004 134 4.8084e−005 0.027 135 0.002 136 0.007 137 0.009 138 0.004 139 0.002 140 0.008 141 0.003 142 0.0002 143 0.001 144 0.007 145 0.005 146 0.0004 147 0.0004 0.438 148 0.001 149 0.001 150 0.0003 151 0.001 152 0.0004 153 0.001 154 0.009 155 0.005 156 0.001 157 0.040 158 1.604 159 4.452 160 0.338 161 0.795 162 0.852 163 6.386 164 2.283 165 3.765 166 0.027 167 0.021 168 0.050 169 0.033 275 0.046 276 0.227 277 0.032 278 0.00164 0.999 279 0.005 280 0.006 281 0.001 282 0.001 292 0.002 293 0.008 294 0.006 295 0.064 298 0.004 299 0.023 0.222 300 0.021 301 0.0005 0.658 302 0.001 304 0.002

-   -   *When compounds were tested more than once, the values have been         reported as averages of their individual experiments.

Example 4 [³⁵S]GTPγS Binding Assay in NG108-15 Cell Membranes (Delta Opioid Functional Assay)-200 nM Screen

Methods: NG108-15 cell membranes were purchased from Applied Cell Sciences (Rockville, Md.). 5 mg/mL of membrane protein was suspended in 10 mM TRIS-HCl pH 7.2, 2 mM EDTA, 10% sucrose. Membranes were maintained at 4-8° C. A 1 mL volume of membranes was added into 10 mL cold binding assay buffer. The assay buffer contained 50 mM Tris, pH 7.6, 5 mM MgCl₂, 100 mM NaCl, 1 mM DTT and 1 mM EGTA. The membrane suspension was homogenized twice with a Polytron, and centrifuged at 3000 rpm for 10 min. The supernatant was then centrifuged at 18,000 rpm for 20 min. Ten mL assay buffer was added into the pellet containing tube. The pellet and buffer were mixed with a Polytron.

Incubation procedure: The pellet membranes (75 μg/mL) were preincubated with SPA (10 mg/mL) at 25° C. for 45 min in the assay buffer. The SPA (5 mg/mL) coupled with membranes (37.5 μg/mL) was then incubated with 0.1 nM [³⁵5] GTPγS in the same Tris buffer containing 100 μM GDP in total volume of 200 μL. 200 nM of receptor agonists was used to stimulate [³⁵5]-GTPγS binding. The basal binding was tested in the absence of agonists and non-specific binding was tested in the presence of 10 μM unlabeled GTPγS. The data were analyzed on a Packard Top Count and are shown in Table 3, below.

DATA

% of Basal=(stimulated−non specific)*100/(basal−non specific).

Relative Efficacy of a compound at 200 nM=(% of Basal of test compound at 200 nM)/(Calculated Max of SNC80 dose response. Curve in prism).

Example 5 [³⁵S]GTPγS Binding Assays in CHO-hMOR Cell Membranes (Mu Opioid Functional Assay)

Methods: CHO-hMOR cell membranes can be purchased from Receptor Biology, Inc. (Baltimore, Md.). About 10 mg/mL of membrane protein can be suspended in 10 mM TRIS-HCl pH 7.2, 2 mM EDTA, 10% sucrose, and the suspension kept on ice. A 1 mL volume of membranes can be added to 15 mL cold binding assay buffer containing 50 mM HEPES, pH 7.6, 5 mM MgCl₂, 100 mM NaCl, 1 mM DTT and 1 mM EDTA. The membrane suspension can be homogenized with a Polytron and centrifuged at 3,000 rpm for 10 min. The supernatant can then be centrifuged at 18,000 rpm for 20 min. The pellet can be resuspended in 10 mL assay buffer with a Polytron. The membranes can be preincubated with wheat germ agglutinin coated SPA beads (Amersham) at 25° C. for 45 min in the assay buffer. The SPA bead (5 mg/mL) coupled membranes (10 μg/mL) can be then incubated with 0.5 nM [³⁵S]GTPγS in the assay buffer. The basal binding can be that taking place in the absence of added test compound; this unmodulated binding can be considered as 100%, with agonist stimulated binding rising to levels significantly above this value. A range of concentrations of receptor agonist can be used to stimulate [³⁵S]GTPγS binding. Both basal and non-specific binding can be tested in the absence of agonist; non-specific binding determination included 10 μM unlabeled GTPγS.

Compounds can be tested for function as antagonists by evaluating their potential to inhibit agonist-stimulated GTPγS binding. Radioactivity can be quantified on a Packard TopCount. The following parameters can be calculated:

${\% \mspace{14mu} {stimulation}} = {\frac{\left( {{{test}\mspace{14mu} {compound}\mspace{14mu} {cpm}} - {{non}\text{-}{specific}\mspace{14mu} {cpm}}} \right)}{\left( {{{basal}\mspace{14mu} {cpm}} - {{non}\text{-}{specific}\mspace{14mu} {cpm}}} \right).} \times 100}$ ${\% \mspace{14mu} {inhibition}} = {\frac{\begin{matrix} {{\% \mspace{14mu} {stimulation}\mspace{14mu} {by}\mspace{14mu} 1\mspace{14mu} µ\; M\mspace{14mu} {DAMGO}} -} \\ {\% \mspace{14mu} {stimulation}\mspace{14mu} {by}\mspace{14mu} {test}\mspace{14mu} {compound}} \end{matrix}}{\left( {{\% \mspace{14mu} {stimulation}\mspace{14mu} {by}\mspace{14mu} 1\mspace{14mu} µ\; M\mspace{14mu} {DAMGO}} - 100} \right)} \times 100}$

EC₅₀ values can be calculated using GraphPad Prism and are shown in Table 3, below.

TABLE 3 Delta and Mu Opioid Receptor Functional Data GTPγS GTPγS δ-opioid GTPγS GTPγS GTPγS GTPγS δ-opioid receptor δ-opioid μ-opioid μ-opioid Cpd δ-RelEfficacy receptor Rel receptor % receptor receptor % No. @200 nM EC₅₀ (μM) Efficacy Inh @10 μm EC₅₀ (μM) Inh @10 μm 2 0.430; 0.733 5.790 0.069 5 0.164 0.803 18.100 7 0.436 0.912 17.066 8 0.0681 0.848 23.626 2.480 9 1.262 0.873 27.407 10 1.164 0.769 24.400 11 0.419 0.818 11.561 12 >10 45.032 13 0.319 0.563 31.369 14 0.313 0.782 15.795 15 0.128 0.503 55.234 16 0.030 0.928 25.532 17 1.734 0.704 16.178 20 0.0162 0.912 33.681 22 0.0393 0.977 20.485 23 0.0416 1.0000 17.675 >10 13.505 24 0.048 0.733 46.235 25 0.0821 0.946 23.384 26 0.069 0.681 5.443 28 0.00810 0.989 4.3964 30 0.025 0.842 20.615 31 0.189 0.996 8.195 32 0.0336 1.0345 12.011 33 0.074 0.828 11.792 34 0.216 0.911 24.781 36 1.489 0.565 12.801 37 3.072 0.882 18.665 38 0.154 0.795 9.115 39 0.370 0.882 1.000 40 0.023 0.521 1.000 41 0.350 0.821 8.514 42 0.182 0.771 20.416 43 0.138 0.831 16.944 44 0.539 0.780 9.315 45 0.128 0.883 1.000 46 0.097 0.708 1.000 47 0.055 0.987 1.000 48 0.076 0.659 4.336 50 0.198 0.961 9.284 51 0.159 0.899 1.000 52 0.008 1.037 1.000 53 0.074 0.870 14.421 54 0.046 0.976 1.444 >10 15.716 55 0.151 0.855 18.315 56 0.536 0.909 26.261 57 0.032 0.828 9.212 58 1.514 0.823 12.772 59 0.433 1.0063 1.478 60 0.089 0.926 3.735 63 0.693 0.993 64 0.088 0.830 12.034 65 0.339 0.824 66 0.568 0.760 5.771 67 0.194 0.944 68 0.031 0.912 11.460 69 0.0085 1.004 >10 22.837 72 0.105 0.905 15.204 73 0.059 0.956 74 0.856 0.868 2.367 80 0.113 1.049 85 >10 86 0.386 0.633 88 0.478 0.538 89 1.315 0.963 90 0.923 1.045 91 >10 92 0.470 1.183 93 0.072 1.115 95 0.708 1.025 96 0.749 0.942 97 7.119 1.128 98 0.106 1.060 99 0.939 1.007 100 1.625 1.019 101 0.103 1.096 >10 16.560 102 0.255 0.989 103 0.311 1.066 104 0.018 0.921 105 0.146 1.099 106 0.027 1.019 >10 16.954 107 1.046 0.0213 0.957 5.100 4.050 109 0.057 1.102 110 0.081 0.986 111 0.491 1.031 112 0.330 1.082 113 0.075 1.104 114 0.306 1.088 115 2.710 1.039 120 121 0.019 1.010 122 123 0.653 0.057 1.124 128 0.453 1.144 129 0.633 0.0551 0.976 130 0.245 131 0.819 0.076 1.063 132 0.015 1.042 9.277 9.396 133 0.755 0.028 1.041 134 0.004 1.087 2.785 1.000 135 1.383 1.023 136 9.005 0.789 137 >10 138 1.340 0.882 139 2.266 1.118 140 0.137 141 0.149 142 0.931 0.029 1.006 143 0.690 1.066 144 0.191 145 4.024 1.180 146 0.387 1.197 147 0.051 1.077 148 0.411 0.158 1.052 149 0.403 0.236 1.026 150 0.801 0.033 1.093 151 0.704 0.119 1.121 152 0.607 0.070 1.083 153 0.454 0.193 1.120 154 0.164 155 0.170 156 0.177 0.967 157 0.213 166 0.169 167 0.328 168 0.300 170 0.176 171 0.257 172 0.246 173 0.249 174 0.205 175 0.005 176 0.112 177 0.511 0.255 1.389 178 0.578 0.300 1.239 179 0.601 0.119 1.182 180 0.250 181 0.139 182 0.470 0.377 1.065 183 0.723 0.091 1.091 184 0.497 0.418 1.271 185 0.447 0.101 1.014 186 0.466 0.331 1.113 187 0.497 0.160 1.104 188 0.779 0.219 1.950 189 0.375 190 0.222 191 0.410 192 0.135 193 0.801 0.032 1.090 194 0.665 0.022 1.034 195 0.477 0.194 1.119 196 0.800 0.0693 1.146 197 0.411 0.145 1.289 198 0.513 0.118 1.050 199 0.615 0.033 1.140 200 0.289 201 0.148 202 0.122 203 0.096 204 0.911 0.026 0.982 205 0.609 0.044 1.178 206 0.292 207 0.963 0.002 1.047 208 0.398 209 0.002 210 0.730 0.044 1.150 211 0.814 0.106 1.050 212 0.161 212 0.658 0.029 0.994 213 0.079 214 0.115 215 0.674 0.128 1.002 216 0.406 0.494 0.969 217 0.480 0.612 0.882 218 0.642 0.353 0.960 219 0.475 >1 220 0.457 0.454 0.890 221 0.324 222 0.284 223 0.802 0.152 0.986 224 0.460 0.214 1.104 225 0.260 0.483 0.718 226 0.320 227 0.480 0.246 1.093 228 1.039 0.006 1.082 229 0.715 0.061 0.890 230 0.847 231 1.159 0.005 1.113 232 0.679 0.143 1.021 233 0.549 234 0.847 0.034 0.987 7.287 235 0.962 0.00733 0.953 236 1.026 0.0170 1.042 6.203 237 3.524 238 0.008 0.966 239 0.348 240 0.376 241 0.381 242 0.413 243 0.433 244 0.354 245 0.0127 1.095 4.259 246 0.078 1.043 248 0.754 0.047 1.084 249 1.000 0.011 0.940 250 0.912 0.026 1.022 251 0.955 0.015 1.145 252 0.025 1.007 2.480 253 0.0168 0.997 254 0.151 0.928 255 0.0464 0.997 17.090 256 0.034 1.004 6.203 257 0.095 0.830 258 0.075 0.835 259 0.0749 1.030 260 0.300 0.937 261 0.241 0.979 262 0.037 0.957 263 0.027 0.869 264 0.120 1.036 265 0.053 1.024 266 0.018 1.041 267 0.121 0.920 268 0.081 1.023 269 0.053 0.984 270 0.197 0.820 271 0.185 0.745 272 >1 273 0.026 1.001 274 0.286 0.863 275 0.922 1.024 276 277 1.092 1.012 278 0.263 279 0.170 1.004 280 0.181 0.998 281 0.221 282 0.349 284 0.600 0.055 0.609 285 0.730 0.027 0.782 286 0.1 287 0.640 288 0.428 289 0.402 290 0.398 291 0.303 292 0.363 0.958 293 0.317 0.975 294 >10 296 0.429 0.938 297 0.424 0.820 298 0.087 1.012 299 0.129 0.840 300 1.052 0.968 301 0.087 1.085 302 0.393 303 0.622 0.114 1.047 304 0.228 305 0.780 0.090 1.081 306 0.910 0.031 1.127 307 0.880 0.011 1.191 308 0.140 309 0.035 1.162 310 0.031 1.042 311 0.0987 0.936 312 0.00435 1.007 313 0.131 1.033 314 0.206 0.840 315 0.042 1.019 316 0.00338 0.977 317 >1 318 0.539 319 0.112 0.871 320 0.191 0.918 321 0.005 1.022 322 0.196 0.960 323 0.060 0.988 324 0.519 0.428 1.045 325 0.866 0.011 1.042 326 0.744 0.032 1.104 327 0.471 0.0527 1.037 4.259 328 0.377 329 0.475 0.138 1.006 330 0.547 0.051 0.894 331 0.764 0.108 0.928 332 0.393 333 0.664 0.118 1.116 334 0.423 335 0.050 336 0.830 0.0502 1.009 17.090 338 0.723 0.197 0.956 339 0.641 341 0.041 0.788 0.000 342 0.0439 1.020 343 0.985 0.001 1.105 1.977 7.287 344 0.808 0.047 1.089 345 0.989 0.001 1.089 1.934 0.000 346 0.0470 1.031 347 0.069 0.898 −0.404 348 0.101 0.689 349 0.082 0.929 0.000 350 0.083 1.079 351 0.0249 1.036 351 0.034 1.056 352 0.079 0.967 353 0.270 0.651 354 0.026 1.050 355 0.022 1.002 0.243 0.000 356 0.031 1.030 357 0.005 0.929 1.831 11.460 358 0.0242 0.978 359 0.034 0.709 360 0.013 1.015 361 0.070 0.962

-   -   *When compounds were tested more than once, the values have been         reported as averages of their individual experiments.

In Vivo Assays Example 6 CFA-Induced Paw Radiant Heat Hypersensitivity

Each rat was placed in a test chamber on a warm glass surface and allowed to acclimate for approximately 10 min. A radiant thermal stimulus (beam of light) was then focused through the glass onto the plantar surface of each hind paw in turn. The thermal stimulus was automatically shut off by a photoelectric relay when the paw was moved or when the cut-off time was reached (20 sec for radiant heat at ˜5 amps). An initial (baseline) response latency to the thermal stimulus was recorded for each animal prior to the injection of complete Freund's adjuvant (CFA). Twenty-four hours following intraplantar CFA injection, the response latency of the animal to the thermal stimulus was then re-evaluated and compared to the animal's baseline response time. Only rats that exhibited at least a 25% reduction in response latency (i.e., were hyperalgesic) were included in further analysis. Immediately following the post-CFA latency assessment, test compound or vehicle (usually Solutol, hydroxypropyl methylcellulose HPMC, hydroxypropyl beta-cyclodextrin HPRCD, or PEG-400) was administered i.p. or p.o. to rats. Post-compound treatment withdrawal latencies were assessed at fixed time intervals, typically 30, 60, 100, 120, 180, and 300 min. The percent reversal (% R) of hypersenstivitiy was calculated according to the following formula:

% reversal=[(treatment response−post CFA response)]/[(baseline response−post CFA response)]×100.

Results are expressed as an average of % reversal values for individual animals, +/−SEM (Standard Error of the Mean).

ED₅₀ values and associated statistics were calculated with PharmTools Pro software (The McCary Group Inc., Schnecksville. PA).

TABLE 4 Time-course studies: The term “Algos” denotes a study run at a contract lab under the same conditions as internal studies) maximum dose route no. of last time % reversal +/− Cpd (mg/kg) vehicle of admin. animals point (min) @ time (min) SEM  8  30 0.5% HPMC p.o. 6 100 49.0 16.4  8 100 0.5% HPMC p.o. 6 100 64.8 10.0  8 100 0.5% HPMC p.o. 7 180 12.5 @ 30′ 54.6 46.5 @ 60′ 34.0  8 100 0.5% HPMC p.o. 9 180 27.7 @ 30′ 17.6  8 100 0.5% HPMC p.o. 10  180 75.1 @ 180′ 17.2 Algos  23 100 0.5% HPMC p.o. 8 240 75.8 @ 120′ 17.6  23 100 0.5% HPMC p.o. 8 120 23.1 @ 120′ 19.1  23 100 0.5% HPMC p.o. 10  180 76.8 @ 120′ 21.3  54 100 0.5% HPMC p.o. 8 120 17.8 @ 60′ 14.1  54 100 0.5% HPMC p.o. 8 180 32.7 @ 180′  8.9  69 100 0.5% HPMC p.o. 8  60 10.1 @ 60′  6.7  69 100 0.5% HPMC p.o. 8 180 55.7 @ 60′ 16.7 Algos  69 100 0.5% HPMC p.o. 8 180 65.4 @ 180′ 15.8 Algos 107 100 0.5% HPMC p.o. 9 240 52.8 @ 120′ 17.3 235  30 0.5% HPMC p.o. 9 240 43.7 @ 60′ 20.1 238  30 0.5% HPMC p.o. 9 240 39.5 @ 60′ 18.4 253  30 0.5% HPMC p.o. 9 240 75.9 @ 60′ 11.9 327  30 0.5% HPMC p.o. 9 240 101.8 @ 60′ 28.2 336  30 0.5% HPMC p.o. 9 120 23.4 @ 30′ 12.6 346  30 0.5% HPMC p.o. 8 120 37.0 @ 30′ 27.1 351  30 0.5% HPMC p.o. 8 120 9.8 @ 30′ 10.3 354  30 0.5% HPMC p.o. 9 120 24.7 @ 60′  5.4

TABLE 5 Dose-response studies: route no. time ED₅₀ doses of of point (mg/ Cpd (mg/kg) vehicle admin. animals (min) kg) SEM 23 10, 30, 100, 0.5% p.o. 8 120 35.35 18.2 300 HPMC 107 10, 30, 100, 0.5% p.o. 8 120 32.0 8.0 300 HPMC 327 3, 10, 30  20% p.o. 8 60 14.3 3.1 HPβCD

Example 7 Mouse Graded Abdominal Irritant Test (GrAIT)

Test compound or vehicle was administered s.c. to mice. Following the pretreatment time, an i.p. injection of 0.6% of acetic acid in 0.5 mL was administered. Five min after acetic acid administration, mice were placed into clear chambers and were continuously observed for 5 min. Behavioral responses including twisting and elongation of the body that extended through the hindlimbs were counted and averaged for the group of animals over the observation period.

TABLE 6 Pre- # abdominal # abdominal dose route of no. of treatment stretches stretches Cpd (mg/kg) vehicle admin. animals (min) (vehicle) (compound)  8 30 10% Solutol s.c. 10 30 20.8 18.9 20 30 10% Solutol s.c. 10 30 14.1 19.8 22 30 10% Solutol s.c. 10 30 19.8 16.0 22 30 10% Solutol s.c. 10 30 13.0 18.6 22 100  10% Solutol s.c. 10 30 19.8 17.4 22 300  10% Solutol s.c. 10 30 19.8 20.3 23 30 10% Solutol s.c. 10 30 13.6 16.7 24 30 10% Solutol s.c. 10 30 15.5 16.9 25 30 10% Solutol s.c. 10 30 15.5 12.3 26 30 10% Solutol s.c. 10 30 13.6 16.7 

1-25. (canceled)
 26. A method for treating mild to severe pain in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula 1

wherein R₁ is selected from the group consisting of i) phenyl optionally substituted with one to two substituents independently selected from the group consisting of C₁₋₄alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl, C₁₋₄alkoxy, C₁₋₄alkylthio, hydroxy, chloro, and fluoro; in addition, phenyl is optionally substituted with a single amino, C₁₋₄alkylamino, di(C₁₋₄alkyl)amino, di(C₁₋₄alkyl)aminocarbonyl, C₁₋₄alkylaminocarbonyl, hydroxy(C₁₋₄)alkyl, aminocarbonyl, C₁₋₄alkylcarbonylamino, C₁₋₄alkoxycarbonylamino, ureido, C₁₋₄alkylureido, di(C₁₋₄alkyl)ureido, cyano, trifluoromethoxy, C₁₋₄alkylsulfonyl, nitro, trifluoromethyl, bromo, piperazin-1-yl optionally substituted with 4-C₁₋₄alkyl, morpholin-4-yl, phenyl, formamido, or pyridinyl substituent; and wherein the phenyl and pyridinyl substituents of the R₁-phenyl are each optionally substituted with one substituent selected from the group consisting of C₁₋₄alkyl, C₁₋₄alkoxy, C₁₋₄alkylthio, fluoro, chloro, cyano, amino, and hydroxy; ii) pyrimidinyl optionally substituted with one to two substituents independently selected from the group consisting of C₁₋₄alkyl, C₁₋₄alkoxy, C₁₋₄alkylthio, and hydroxy; in addition, pyrimidinyl is optionally substituted with a single amino, C₁₋₄alkylamino, di(C₁₋₄alkyl)amino, di(C₁₋₄alkyl)aminocarbonyl, C₁₋₄alkylaminocarbonyl, hydroxy(C₁₋₄)alkyl, aminocarbonyl, C₁₋₄alkylcarbonylamino, C₁₋₄alkoxycarbonylamino, ureido, C₁₋₄alkylureido, di(C₁₋₄alkyl)ureido, cyano, trifluoromethoxy, C₁₋₄alkylsulfonyl, nitro, trifluoromethyl, bromo, piperazin-1-yl optionally substituted with 4-C₁₋₄alkyl, morpholin-4-yl, formamido, pyrrol-1-yl, phenyl, pyridinyl or piperidin-1-yl substituent; and wherein the phenyl and pyridinyl substituents of the R₁-pyrimidinyl are each optionally substituted with one substituent selected from the group consisting of C₁₋₄alkyl, C₁₋₄alkoxy, C₁₋₄alkylthio, fluoro, chloro, cyano, amino, and hydroxy; iii) pyridinyl optionally substituted with one to two substituents independently selected form the group consisting of C₁₋₄alkyl, C₁₋₄alkoxy, C₁₋₄alkylthio, hydroxy, fluoro, chloro, and cyano; in addition, pyridinyl is optionally substituted with a single hydroxymethyl, amino, C₁₋₄alkylamino, di(C₁₋₄alkyl)amino, C₁₋₄alkylsulfonyl, aminocarbonyl, C₁₋₄alkylaminocarbonyl, di(C₁₋₄alkyl)aminocarbonyl, C₁₋₄alkylcarbonylamino, C₁₋₄alkoxyaminocarbonyl, ureido, C₁₋₄alkylureido, di(C₁₋₄alkyl)ureido, piperazin-1-yl, morpholin-4-yl, phenyl, or pyridinyl; and, wherein the phenyl and pyridinyl substituents of the R₁-pyridinyl are optionally independently substituted with one to two substituents selected from the group consisting of C₁₋₄alkyl, C₁₋₄alkoxy, C₁₋₄alkylthio, fluoro, chloro, cyano, amino, and hydroxy; and iv) a G-substituent selected from the group consisting of naphthyl, pyrazolyl, thienyl, benzothiazolyl, benzimidazolyl, quinolinyl, indolyl, thiazolyl, furanyl, dihydrobenzofuranyl, pyrazinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, isoxazolyl, oxazolyl, pyrrolopyridinyl, benzo[1,3]dioxol-5-yl, benzo[1,2,5]oxadiazolyl, dibenzothiophenyl, 4H-[1,2,4]oxadiazol-5-on-yl, benzothiophenyl, indazolyl, and 2,3-dihydrobenzo[1,4]dioxinyl; wherein G is optionally independently substituted with one to two substituents selected from the group consisting of C₁₋₄alkyl, C₁₋₄alkoxy, fluoro, chloro, bromo, cyano, C₁₋₄alkylcarbonyl, amino, C₁₋₄alkylamino, and di(C₁₋₄alkyl)amino; R₂ is (i) phenyl optionally substituted with one to three substituents independently selected from the group consisting of C₁₋₄alkyl, C₁₋₄alkoxy, C₁₋₄alkylthio, fluoro, chloro, and hydroxy; in addition, phenyl of R₂ is optionally substituted with a single amino, C₁₋₄alkylamino, di(C₁₋₄alkyl)amino, fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, formamidino, aminocarbonyl, C₁₋₄alkylaminocarbonyl, di(C₁₋₄)alkylaminocarbonyl, C₁₋₄alkylcarbonylamino, 2,2,2-trifluoroethoxy, cyano, C₃₋₇cycloalkylcarbonylamino, hydroxy(C₁₋₄)alkyl, C₁₋₄alkoxy(C₁₋₄alkyl, C₁₋₄alkoxy-(C₁₋₄)alkoxy, C₁₋₄alkylcarbonyloxy, C₁₋₄alkylsulfonylamino, C₁₋₄alkylsulfonyl, pyridinyl(C₁₋₄alkyl, benzyloxycarbonylamino, 4-methyl-piperazin-1-ylcarbonyl, pyrrolidin-1-ylcarbonyl, carboxy, piperidin-1-ylcarbonyl, morpholin-4-ylcarbonyl, C₃₋₇cycloalkyl, C₃₋₇cycloalkyl-(C₁₋₃)alkyl, or C₃₋₇cycloalkyl-(C₁₋₃)alkoxy substituent; (ii) 1,2-dihydrobenzofuranyl; provided that 1,2-dihydrobenzofuranyl is bound to O of Formula (I) at the benzo portion of the ring; and wherein the benzo portion of 1,2-dihydrobenzofuranyl is optionally independently substituted with one to two substituents selected from the group consisting of C₁₋₄alkyl, fluoro, chloro, bromo, cyano, C₁₋₄alkylcarbonyl, amino, C₁₋₄alkylamino, and di(C₁₋₄alkylamino; or (iii) heteroaryl selected from the group consisting of benzothiazolyl, benzooxazolyl, pyridinyl, pyrimidinyl, indazolyl, quinolinyl, quinazolinyl, benzimidazolyl, pyrazinyl, triazinyl, benzothiophenyl, benzofuranyl, and isoquinolinyl; wherein heteroaryl of R₂ is optionally independently substituted with one to two substituents selected from the group consisting of C₁₋₄alkyl, fluoro, chloro, bromo, cyano, C₁₋₄alkylcarbonyl, amino, C₁₋₄alkylamino, and di(C₁₋₄alkylamino; A-L- is selected from the group consisting of a₁-L₁-; a_(z)-L₂-; a₃-L₃-; a₄-L₄-; and a₅-L₅-; wherein L₁ is absent or C₁₋₄alkyl; a₁ is bound through a carbon atom to L₁ and is selected from the group consisting of i) pyrrolidinyl optionally substituted at carbon with C₁₋₄alkyl, amino, C₁₋₄alkylamino, di(C₁₋₄alkyl)amino, aminomethyl, hydroxy, cyano, C₁₋₄alkoxy, C₁₋₄alkoxycarbonyl, or one to two fluoro substituents; and wherein pyrrolidinyl is optionally substituted at nitrogen with C₁₋₄alkyl, phenyl(C₁₋₄alkyl, C₁₋₄alkylcarbonyl, C₁₋₄alkoxycarbonyl, or phenyl(C₁₋₄)alkoxycarbonyl; ii) piperidinyl optionally substituted with C₁₋₄alkyl, phenyl, amino, C₁₋₄alkylamino, di(C₁₋₄alkyl)amino, aminomethyl, hydroxy, cyano, C₁₋₄alkoxy, C₁₋₄alkoxycarbonyl, phenyl(C₁₋₄)alkyl, C₁₋₄alkylcarbonyl, or phenyl(C₁₋₄)alkoxycarbonyl; and iii) azetidinyl optionally substituted with 3-amino, 3-hydroxy, 3-C₁₋₄alkoxy, C₁₋₄alkyl, or aminomethyl; provided that when L₁ is absent, a₁ is attached to N(R_(a)) via a carbon atom other than that which is alpha to a nitrogen atom of a₁; and provided that when a₁ is substituted with a substituent containing an oxygen or nitrogen radical as a point of attachment to a₁, the substitution is at a carbon atom other than that alpha to a nitrogen atom of a₁; L₂ is C₁₋₄alkyl; a₂ is bound through a carbon atom to L₂ and is selected from the group consisting of i) piperazinyl optionally substituted at carbon with C₁₋₄alkyl, aminomethyl, cyano, or C₁₋₄alkoxycarbonyl; and wherein piperazinyl is optionally substituted at nitrogen with C₁₋₄alkyl, phenyl(C₁₋₄)alkyl, C₁₋₄alkylcarbonyl, C₁₋₄alkoxycarbonyl, or phenyl(C₁₋₄)alkoxycarbonyl; and iii) morpholinyl optionally independently substituted with phenyl(C₁₋₄)alkyl or one to two C₁₋₄alkyl substituents; L₃ is methylene; a₃ is imidazolyl optionally independently substituted with one to two C₁₋₄alkyl substituents; L₄ is (C₂₋₆)alkyl; and when L₄ is C₃₋₆alkyl, L₄ is optionally substituted with chloro, hydroxy or C₁₋₄alkoxy; provided that the chloro, hydroxy, and C₁₋₄alkoxy substituents are not alpha to a nitrogen-bearing carbon atom; a₄ is selected from the group consisting of amino and C₁₋₄alkylamino; provided that a₄ is attached at a carbon atom other than that alpha to N(R_(a)); L₅ is absent or C₁₋₄alkyl; a₅ is C₃₋₇cycloalkyl substituted with R_(B); wherein R_(B) is selected from the group consisting of amino, C₁₋₄alkylamino, di(C₁₋₄alkyl)amino, aminomethyl, C₁₋₄alkylamino-methyl, and di(C₁₋₄alkyl)amino-methyl; provided that when R_(B) contains a nitrogen radical as the point of attachment to C₃₋₇cycloalkyl, the attachment is at a carbon atom other than that alpha to N(R_(a)); or, A-L- is taken with R_(a) and the nitrogen atom to which they are both attached to form a nitrogen-bound heterocyclyl selected from the group consisting of i) pyrrolidinyl wherein pyrrolidinyl is optionally substituted with C₁₋₄alkyl, amino, C₁₋₄alkylamino, di(C₁₋₄alkyl)amino, aminomethyl, cyano, C₁₋₄alkoxy, C₁₋₄alkoxycarbonyl, or phenyl; ii) piperazinyl optionally substituted with 4-C₁₋₄alkyl; and wherein piperazinyl is optionally independently substituted at carbon with one to two C₁₋₄alkyl substituents, 2-oxo, 3-oxo, trifluoromethyl, aminomethyl, or hydroxymethyl iii) piperidinyl optionally substituted with one to two C₁₋₄alkyl substituents, amino, C₁₋₄alkylamino, di(C₁₋₄alkyl)amino, aminomethyl, hydroxy, cyano, C₁₋₄alkoxy, C₁₋₄alkoxycarbonyl, phenyl, phenyl(C₁₋₄)alkyl, or one to two fluoro substituents; and, wherein the phenyl and the phenyl portion of phenyl(C₁₋₄)alkyl are optionally substituted with C₁₋₄alkyl, C₁₋₄alkoxy, C₁₋₄alkylthio, fluoro, chloro, cyano, amino, or hydroxy; iv) azetidinyl optionally substituted with 3-amino or 3-aminomethyl; v) [1,4]diazepan-1-yl optionally substituted with one to two C₁₋₄alkyl substituents; and vi) 3,6-diazoabicyclo[3.1.1]hept-3-yl optionally substituted with one to two C₁₋₄alkyl substituents; R_(a) is hydrogen or C₁₋₄alkylcarbonyl; provided that a compound of Formula (I) is other than a compound selected from the group consisting of a compound wherein R₁ is 4-fluoro-phenyl, R₂ is 4-methoxy-phenyl, A-L- is a₁-L₁, a₁ is (S)-pyrrolidin-2-yl, L₁ is methyl, R_(a) is H, and X is O; a compound wherein R₁ is pyrimidin-5-yl, R₂ is 4-methoxy-phenyl, A-L- is a₂-L₂, a₂ is (S)-morpholin-3-yl, L₂ is methyl, R_(a) is H, and X is O; a compound wherein R₁ is 5-fluoro-pyridin-3-yl, R₂ is 4-(piperidin-1-ylcarbonyl)-phenyl, A-L- is a₁-L₁, a₁ is (S)-pyrrolidin-2-yl, L₁ is methyl, R_(a) is H, and X is O; a compound wherein R₁ is 5-fluoro-pyridin-3-yl, R₂ is 4-(4-methyl-piperazin-1-ylcarbonyl)-phenyl, A-L- is a₁-L₁, a₁ is (S)-pyrrolidin-2-yl, L₁ is methyl, R_(a) is H, and X is O; a compound wherein R₁ is 5-cyano-pyridin-3-yl, R₂ is 2-methyl-phenyl, A-L- is a₁-L₁, a₁ is (S)-pyrrolidin-2-yl, L₁ is methyl, R_(a) is H, and X is O; a compound wherein R₁ is pyridin-3-yl, R₂ is 4-methoxy-phenyl, A-L- is a₅-L₅, a₅ is cyclohexyl, L₅ is absent, R_(B) is 2-amino, R_(a) is H, and X is O; and a compound wherein R₁ is 5-fluoro-pyridin-3-yl, R₂ is 4-diethylaminocarbonyl-phenyl, A-L- is a₁-L₁, a₁ is (S)-pyrrolidin-2-yl, L₁ is methyl, R_(a) is H, and X is O; and enantiomers, diastereomers, and pharmaceutically acceptable salts thereof.
 27. The method of claim 26 wherein the mild to severe pain is due to a disease or condition selected from the group consisting of osteoarthritis, rheumatoid arthritis, fibromyalgia, migraine, headache, toothache, burn, sunburn, snake bite, spider bite, insect sting, neurogenic bladder, benign prostatic hypertrophy, interstitial cystitis, rhinitis, contact dermatitis/hypersensitivity, itch, eczema, pharyngitis, mucositis, enteritis, cellulites, causalgia, sciatic neuritis, mandibular joint neuralgia, peripheral neuritis, polyneuritis, stump pain, phantom limb pain, post operative ileus, cholecystitis, postmastectomy pain syndrome, oral neuropathic pain, Charcot's pain, reflex sympathetic dystrophy, Guillain Barre syndrome, meralgia paresthetica, burning mouth syndrome, cluster headache, migraine headache, peripheral neuropathy, bilateral peripheral neuropathy, diabetic neuropathy, optic neuritis, postfebrile neuritis, migrating neuritis, segmental neuritis, Gombault's neuritis, neuronitis, cervicobrachial neuralgia, cranial neuralgia, geniculate neuralgia, glossopharyngial neuralgia, migrainous neuralgia, idiopathic neuralgia, intercostals neuralgia, mammary neuralgia, Morton's neuralgia, nasociliary neuralgia, occipital neuralgia, red neuralgia, Sluder's neuralgia, splenopalatine neuralgia, supraorbital neuralgia, vidian neuralgia, inflammatory bowel disease, irritable bowel syndrome, sinus headache, tension headache, labor, childbirth, menstrual cramps, and cancer.
 28. The method of claim 26 wherein the pain is selected from the group consisting of inflammatory pain, centrally mediated pain, peripherally mediated pain, visceral pain, structural related pain, cancer pain, soft tissue injury related pain, progressive disease related pain, neuropathic pain and acute pain from acute injury, acute pain from trauma, acute pain from surgery, chronic pain from headache, chronic pain from neuropathic conditions, chronic pain from post stroke conditions and chronic pain from migraine.
 29. A method for treating or preventing a disease or condition selected from the group consisting of depression, Parkinson's disease, drug abuse, alcohol abuse, gastritis, urinary incontinence, premature ejaculation, diarrhea, cardiovascular disease, and respiratory diseases, said method comprising the step of administering to a mammal in need of such treatment a therapeutically effective amount of a compound, or salt of Formula I

wherein R₁ is selected from the group consisting of iv) phenyl optionally substituted with one to two substituents independently selected from the group consisting of C₁₋₄alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl, C₁₋₄alkoxy, C₁₋₄alkylthio, hydroxy, chloro, and fluoro; in addition, phenyl is optionally substituted with a single amino, C₁₋₄alkylamino, di(C₁₋₄alkyl)amino, di(C₁₋₄alkyl)aminocarbonyl, C₁₋₄alkylaminocarbonyl, hydroxy(C₁₋₄alkyl, aminocarbonyl, C₁₋₄alkylcarbonylamino, C₁₋₄alkoxycarbonylamino, ureido, C₁₋₄alkylureido, di(C₁₋₄alkyl)ureido, cyano, trifluoromethoxy, C₁₋₄alkylsulfonyl, nitro, trifluoromethyl, bromo, piperazin-1-yl optionally substituted with 4-C₁₋₄alkyl, morpholin-4-yl, phenyl, formamido, or pyridinyl substituent; and wherein the phenyl and pyridinyl substituents of the R₁-phenyl are each optionally substituted with one substituent selected from the group consisting of C₁₋₄alkyl, C₁₋₄alkoxy, C₁₋₄alkylthio, fluoro, chloro, cyano, amino, and hydroxy; v) pyrimidinyl optionally substituted with one to two substituents independently selected from the group consisting of C₁₋₄alkyl, C₁₋₄alkoxy, C₁₋₄alkylthio, and hydroxy; in addition, pyrimidinyl is optionally substituted with a single amino, C₁₋₄alkylamino, di(C₁₋₄alkyl)amino, di(C₁₋₄alkyl)aminocarbonyl, C₁₋₄alkylaminocarbonyl, hydroxy(C₁₋₄)alkyl, aminocarbonyl, C₁₋₄alkylcarbonylamino, C₁₋₄alkoxycarbonylamino, ureido, C₁₋₄alkylureido, di(C₁₋₄alkyl)ureido, cyano, trifluoromethoxy, C₁₋₄alkylsulfonyl, nitro, trifluoromethyl, bromo, piperazin-1-yl optionally substituted with 4-C₁₋₄alkyl, morpholin-4-yl, formamido, pyrrol-1-yl, phenyl, pyridinyl or piperidin-1-yl substituent; and wherein the phenyl and pyridinyl substituents of the R₁-pyrimidinyl are each optionally substituted with one substituent selected from the group consisting of C₁₋₄alkyl, C₁₋₄alkoxy, C₁₋₄alkylthio, fluoro, chloro, cyano, amino, and hydroxy; iii) pyridinyl optionally substituted with one to two substituents independently selected form the group consisting of C₁₋₄alkyl, C₁₋₄alkoxy, C₁₋₄alkylthio, hydroxy, fluoro, chloro, and cyano; in addition, pyridinyl is optionally substituted with a single hydroxymethyl, amino, C₁₋₄alkylamino, di(C₁₋₄alkyl)amino, C₁₋₄alkylsulfonyl, aminocarbonyl, C₁₋₄alkylaminocarbonyl, di(C₁₋₄alkyl)aminocarbonyl, C₁₋₄alkylcarbonylamino, C₁₋₄alkoxyaminocarbonyl, ureido, C₁₋₄alkylureido, di(C₁₋₄alkyl)ureido, piperazin-1-yl, morpholin-4-yl, phenyl, or pyridinyl; and, wherein the phenyl and pyridinyl substituents of the R₁-pyridinyl are optionally independently substituted with one to two substituents selected from the group consisting of C₁₋₄alkyl, C₁₋₄alkoxy, C₁₋₄alkylthio, fluoro, chloro, cyano, amino, and hydroxy; and iv) a G-substituent selected from the group consisting of naphthyl, pyrazolyl, thienyl, benzothiazolyl, benzimidazolyl, quinolinyl, indolyl, thiazolyl, furanyl, dihydrobenzofuranyl, pyrazinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, isoxazolyl, oxazolyl, pyrrolopyridinyl, benzo[1,3]dioxol-5-yl, benzo[1,2,5]oxadiazolyl, dibenzothiophenyl, 4H-[1,2,4]oxadiazol-5-on-yl, benzothiophenyl, indazolyl, and 2,3-dihydrobenzo[1,4]dioxinyl; wherein G is optionally independently substituted with one to two substituents selected from the group consisting of C₁₋₄alkyl, C₁₋₄alkoxy, fluoro, chloro, bromo, cyano, C₁₋₄alkylcarbonyl, amino, C₁₋₄alkylamino, and di(C₁₋₄alkyl)amino; R₂ is (iv) phenyl optionally substituted with one to three substituents independently selected from the group consisting of C₁₋₄alkyl, C₁₋₄alkoxy, C₁₋₄alkylthio, fluoro, chloro, and hydroxy; in addition, phenyl of R₂ is optionally substituted with a single amino, C₁₋₄alkylamino, di(C₁₋₄alkyl)amino, fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, formamidino, aminocarbonyl, C₁₋₄alkylaminocarbonyl, di(C₁₋₄alkylaminocarbonyl, C₁₋₄alkylcarbonylamino, 2,2,2-trifluoroethoxy, cyano, C₃₋₇cycloalkylcarbonylamino, hydroxy(C₁₋₄)alkyl, C₁₋₄alkoxy(C₁₋₄alkyl, C₁₋₄alkoxy-(C₁₋₄)alkoxy, C₁₋₄alkylcarbonyloxy, C₁₋₄alkylsulfonylamino, C₁₋₄alkylsulfonyl, pyridinyl(C₁₋₄alkyl, benzyloxycarbonylamino, 4-methyl-piperazin-1-ylcarbonyl, pyrrolidin-1-ylcarbonyl, carboxy, piperidin-1-ylcarbonyl, morpholin-4-ylcarbonyl, C₃₋₇cycloalkyl, C₃₋₇cycloalkyl-(C₁₋₃)alkyl, or C₃₋₇cycloalkyl-(C₁₋₃)alkoxy substituent; (v) 1,2-dihydrobenzofuranyl; provided that 1,2-dihydrobenzofuranyl is bound to O of Formula (I) at the benzo portion of the ring; and wherein the benzo portion of 1,2-dihydrobenzofuranyl is optionally independently substituted with one to two substituents selected from the group consisting of C₁₋₄alkyl, fluoro, chloro, bromo, cyano, C₁₋₄alkylcarbonyl, amino, C₁₋₄alkylamino, and di(C₁₋₄alkylamino; or (vi) heteroaryl selected from the group consisting of benzothiazolyl, benzooxazolyl, pyridinyl, pyrimidinyl, indazolyl, quinolinyl, quinazolinyl, benzimidazolyl, pyrazinyl, triazinyl, benzothiophenyl, benzofuranyl, and isoquinolinyl; wherein heteroaryl of R₂ is optionally independently substituted with one to two substituents selected from the group consisting of C₁₋₄alkyl, fluoro, chloro, bromo, cyano, C₁₋₄alkylcarbonyl, amino, C₁₋₄alkylamino, and di(C₁₋₄alkylamino; A-L- is selected from the group consisting of a₁-L₁-; a₂-L₂-; a₃-L₃-; a₄-L₄-; and a₅-L₅-; wherein L₁ is absent or C₁₋₄alkyl; a₁ is bound through a carbon atom to L₁ and is selected from the group consisting of i) pyrrolidinyl optionally substituted at carbon with C₁₋₄alkyl, amino, C₁₋₄alkylamino, di(C₁₋₄alkyl)amino, aminomethyl, hydroxy, cyano, C₁₋₄alkoxy, C₁₋₄alkoxycarbonyl, or one to two fluoro substituents; and wherein pyrrolidinyl is optionally substituted at nitrogen with C₁₋₄alkyl, phenyl(C₁₋₄alkyl, C₁₋₄alkylcarbonyl, C₁₋₄alkoxycarbonyl, or phenyl(C₁₋₄)alkoxycarbonyl; ii) piperidinyl optionally substituted with C₁₋₄alkyl, phenyl, amino, C₁₋₄alkylamino, di(C₁₋₄alkyl)amino, aminomethyl, hydroxy, cyano, C₁₋₄alkoxy, C₁₋₄alkoxycarbonyl, phenyl(C₁₋₄)alkyl, C₁₋₄alkylcarbonyl, or phenyl(C₁₋₄)alkoxycarbonyl; and iii) azetidinyl optionally substituted with 3-amino, 3-hydroxy, 3-C₁₋₄alkoxy, C₁₋₄alkyl, or aminomethyl; provided that when L₁ is absent, a₁ is attached to N(R_(a)) via a carbon atom other than that which is alpha to a nitrogen atom of a₁; and provided that when a₁ is substituted with a substituent containing an oxygen or nitrogen radical as a point of attachment to a₁, the substitution is at a carbon atom other than that alpha to a nitrogen atom of a₁; L₂ is C₁₋₄alkyl; a₂ is bound through a carbon atom to L₂ and is selected from the group consisting of i) piperazinyl optionally substituted at carbon with C₁₋₄alkyl, aminomethyl, cyano, or C₁₋₄alkoxycarbonyl; and wherein piperazinyl is optionally substituted at nitrogen with C₁₋₄alkyl, phenyl(C₁₋₄)alkyl, C₁₋₄alkylcarbonyl, C₁₋₄alkoxycarbonyl, or phenyl(C₁₋₄)alkoxycarbonyl; and vi) morpholinyl optionally independently substituted with phenyl(C₁₋₄)alkyl or one to two C₁₋₄alkyl substituents; L₃ is methylene; a₃ is imidazolyl optionally independently substituted with one to two C₁₋₄alkyl substituents; L₄ is (C₂₋₆)alkyl; and when L₄ is C₃₋₆alkyl, L₄ is optionally substituted with chloro, hydroxy or C₁₋₄alkoxy; provided that the chloro, hydroxy, and C₁₋₄alkoxy substituents are not alpha to a nitrogen-bearing carbon atom; a₄ is selected from the group consisting of amino and C₁₋₄alkylamino; provided that a₄ is attached at a carbon atom other than that alpha to N(R_(a)); L₅ is absent or C₁₋₄alkyl; a₅ is C₃₋₇cycloalkyl substituted with R_(B); wherein R_(B) is selected from the group consisting of amino, C₁₋₄alkylamino, di(C₁₋₄alkyl)amino, aminomethyl, C₁₋₄alkylamino-methyl, and di(C₁₋₄alkyl)amino-methyl; provided that when R_(B) contains a nitrogen radical as the point of attachment to C₃₋₇cycloalkyl, the attachment is at a carbon atom other than that alpha to N(R_(a)); or, A-L- is taken with R_(a) and the nitrogen atom to which they are both attached to form a nitrogen-bound heterocyclyl selected from the group consisting of i) pyrrolidinyl wherein pyrrolidinyl is optionally substituted with C₁₋₄alkyl, amino, C₁₋₄alkylamino, di(C₁₋₄alkyl)amino, aminomethyl, cyano, C₁₋₄alkoxy, C₁₋₄alkoxycarbonyl, or phenyl; ii) piperazinyl optionally substituted with 4-C₁₋₄alkyl; and wherein piperazinyl is optionally independently substituted at carbon with one to two C₁₋₄alkyl substituents, 2-oxo, 3-oxo, trifluoromethyl, aminomethyl, or hydroxymethyl iii) piperidinyl optionally substituted with one to two C₁₋₄alkyl substituents, amino, C₁₋₄alkylamino, di(C₁₋₄alkyl)amino, aminomethyl, hydroxy, cyano, C₁₋₄alkoxy, C₁₋₄alkoxycarbonyl, phenyl, phenyl(C₁₋₄)alkyl, or one to two fluoro substituents; and, wherein the phenyl and the phenyl portion of phenyl(C₁₋₄)alkyl are optionally substituted with C₁₋₄alkyl, C₁₋₄alkoxy, C₁₋₄alkylthio, fluoro, chloro, cyano, amino, or hydroxy; iv) azetidinyl optionally substituted with 3-amino or 3-aminomethyl; v) [1,4]diazepan-1-yl optionally substituted with one to two C₁₋₄alkyl substituents; and vi) 3,6-diazoabicyclo[3.1.1]hept-3-yl optionally substituted with one to two C₁₋₄alkyl substituents; R_(a) is hydrogen or C₁₋₄alkylcarbonyl; provided that a compound of Formula (I) is other than a compound selected from the group consisting of a compound wherein R₁ is 4-fluoro-phenyl, R₂ is 4-methoxy-phenyl, A-L- is a₁-L₁, a₁ is (S)-pyrrolidin-2-yl, L₁ is methyl, R_(a) is H, and X is O; a compound wherein R₁ is pyrimidin-5-yl, R₂ is 4-methoxy-phenyl, A-L- is a₂-L₂, a₂ is (S)-morpholin-3-yl, L₂ is methyl, R_(a) is H, and X is O; a compound wherein R₁ is 5-fluoro-pyridin-3-yl, R₂ is 4-(piperidin-1-ylcarbonyl)-phenyl, A-L- is a₁-L₁, a₁ is (S)-pyrrolidin-2-yl, L₁ is methyl, R_(a) is H, and X is O; a compound wherein R₁ is 5-fluoro-pyridin-3-yl, R₂ is 4-(4-methyl-piperazin-1-ylcarbonyl)-phenyl, A-L- is a₁-L₁, a₁ is (S)-pyrrolidin-2-yl, L₁ is methyl, R_(a) is H, and X is O; a compound wherein R₁ is 5-cyano-pyridin-3-yl, R₂ is 2-methyl-phenyl, A-L- is a₁-L₁, a₁ is (S)-pyrrolidin-2-yl, L₁ is methyl, R_(a) is H, and X is O; a compound wherein R₁ is pyridin-3-yl, R₂ is 4-methoxy-phenyl, A-L- is a₅-L₅, a₅ is cyclohexyl, L₅ is absent, R_(B) is 2-amino, R_(a) is H, and X is O; and a compound wherein R₁ is 5-fluoro-pyridin-3-yl, R₂ is 4-diethylaminocarbonyl-phenyl, A-L- is a₁-L₁, a₁ is (S)-pyrrolidin-2-yl, L₁ is methyl, R_(a) is H, and X is O; and enantiomers, diastereomers, and pharmaceutically acceptable salts thereof. 